WO1982000588A1 - 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 Download PDF

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Publication number
WO1982000588A1
WO1982000588A1 PCT/US1981/001103 US8101103W WO8200588A1 WO 1982000588 A1 WO1982000588 A1 WO 1982000588A1 US 8101103 W US8101103 W US 8101103W WO 8200588 A1 WO8200588 A1 WO 8200588A1
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WO
WIPO (PCT)
Prior art keywords
interferon
species
cells
isolated
bovine
Prior art date
Application number
PCT/US1981/001103
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English (en)
Inventor
Illinois Univ
J Cummins
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Illinois Univ
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Application filed by Illinois Univ filed Critical Illinois Univ
Publication of WO1982000588A1 publication Critical patent/WO1982000588A1/fr

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Classifications

    • 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
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • 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).
  • 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.
  • “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:
  • 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
  • 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.
  • 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.
  • 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.

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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.
PCT/US1981/001103 1980-08-22 1981-08-18 Administration de composants biologiquement actifs d'isolats d'interferons d'especes heterologues WO1982000588A1 (fr)

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US18046480A 1980-08-22 1980-08-22
US180464800822 1980-08-22

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JP (1) JPS57501236A (fr)
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3345092A1 (de) * 1982-12-13 1984-06-14 The Texas A & M University System, College Station, Tex. Verfahren zur beeinflussung des appetits von tieren
FR2575655A1 (fr) * 1985-01-04 1986-07-11 Texas A & M Univ Sys Utilisation d'un interferon a faibles doses notamment pour regler l'appetit et l'efficacite de l'utilisation des aliments
WO1987004076A1 (fr) * 1985-12-30 1987-07-16 The Texas A & M University System Faible dosage d'interferon pour ameliorer l'efficacite d'un vaccin
EP0341258A1 (fr) * 1986-11-06 1989-11-15 Amarillo Cell Culture Co Composition pharmaceutique contenant de l'interféron pour une administration buccale.
EP0396616A1 (fr) * 1988-01-06 1990-11-14 Amarillo Cell Culture Co Reduction des effets secondaires de la therapie du cancer.
US5817307A (en) * 1986-11-06 1998-10-06 The Texas A&M University System Treatment of bacterial infection with oral interferon-α
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
EP0898478A1 (fr) * 1996-05-09 1999-03-03 Pharma Pacific Pty. Ltd. Stimulation des mecanismes de defense d'hotes contre les tumeurs
US5997858A (en) * 1996-05-09 1999-12-07 Pharma Pacific Pty Ltd. Stimulation of host defense mechanisms against tumors
US6207145B1 (en) 1997-05-09 2001-03-27 Pharma Pacific Pty Ltd. Therapeutic applications of high dose interferon
US6361769B1 (en) 1996-05-09 2002-03-26 Pharma Pacific Pty Ltd Stimulation of host defense mechanisms against viral challenges
US6660258B1 (en) 1997-05-09 2003-12-09 Pharma Pacific Pty Ltd Oromucosal cytokine compositions and uses thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990007618A1 (fr) * 1988-12-28 1990-07-12 Toshiro Suzuki Materiau de construction en beton

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4273703A (en) * 1977-11-01 1981-06-16 Ess-Food Eksport-Svineslagteriernes Salgsforening Interferon product and process for its preparation

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4273703A (en) * 1977-11-01 1981-06-16 Ess-Food Eksport-Svineslagteriernes Salgsforening Interferon product and process for its preparation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Journal of American Medical Association, Volume 245, No. 2, issued 1981 (U.S.), JOHNSON, "Interferon: Cloudy but Intriguing Future". *
Pharmacology and Therapeutics, Volume 2, No. 4, issued 1978 (Great Britain), POLLARD and MERIGAN, "Experience with Clinical Applications of Interferon and Inducers", see pages 783-811. *
Pharmacology and Therapeutics, Volume 8, No. 2, issued 1980 (Great Britain), CARTER and HOROSZEWICZ, "Production, Purification and Clinical Application of Huan Fibroblast Interferon", see pages 367-374. *

Cited By (23)

* 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
DE3345092A1 (de) * 1982-12-13 1984-06-14 The Texas A & M University System, College Station, Tex. Verfahren zur beeinflussung des appetits von tieren
FR2537436A1 (fr) * 1982-12-13 1984-06-15 Texas A & M Univ Sys Procede de regulation de l'appetit et de l'efficacite de l'utilisation des aliments utilisant de l'interferon
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
FR2575655A1 (fr) * 1985-01-04 1986-07-11 Texas A & M Univ Sys Utilisation d'un interferon a faibles doses notamment pour regler l'appetit et l'efficacite de l'utilisation des aliments
WO1987004076A1 (fr) * 1985-12-30 1987-07-16 The Texas A & M University System Faible dosage d'interferon pour ameliorer l'efficacite d'un vaccin
US5824300A (en) * 1986-11-06 1998-10-20 The Texas A&M University System Treatment of neoplastic disease with oral interferon
US5846526A (en) * 1986-11-06 1998-12-08 The Texas A&M University System Treatment of autoimmune disorders with oral interferon
US5817307A (en) * 1986-11-06 1998-10-06 The Texas A&M University System Treatment of bacterial infection with oral interferon-α
US6372218B1 (en) 1986-11-06 2002-04-16 The Texas A&M University System Interferon dosage form and method therefor
EP0341258A4 (en) * 1986-11-06 1990-10-10 Amarillo Cell Culture Company, Inc. Improved interferon therapy
US5830456A (en) * 1986-11-06 1998-11-03 The Texas A&M University System Treatment of viral disease with oral interferon-α
EP0341258A1 (fr) * 1986-11-06 1989-11-15 Amarillo Cell Culture Co Composition pharmaceutique contenant de l'interféron pour une administration buccale.
US5882640A (en) * 1986-11-06 1999-03-16 The Texas A&M University System Treatment of hyperallergenic response with oral interferon
EP0396616A4 (en) * 1988-01-06 1991-10-16 Amarillo Cell Culture Company, Inc. Reduction of side effects of cancer therapy
EP0396616A1 (fr) * 1988-01-06 1990-11-14 Amarillo Cell Culture Co Reduction des effets secondaires de la therapie du cancer.
EP0898478A1 (fr) * 1996-05-09 1999-03-03 Pharma Pacific Pty. Ltd. Stimulation des mecanismes de defense d'hotes contre les tumeurs
EP0898478A4 (fr) * 1996-05-09 1999-05-26 Pharma Pacific Pty Ltd Stimulation des mecanismes de defense d'hotes contre les tumeurs
US5997858A (en) * 1996-05-09 1999-12-07 Pharma Pacific Pty Ltd. Stimulation of host defense mechanisms against tumors
US6361769B1 (en) 1996-05-09 2002-03-26 Pharma Pacific Pty Ltd Stimulation of host defense mechanisms against viral challenges
US6207145B1 (en) 1997-05-09 2001-03-27 Pharma Pacific Pty Ltd. Therapeutic applications of high dose interferon
US6660258B1 (en) 1997-05-09 2003-12-09 Pharma Pacific Pty Ltd Oromucosal cytokine compositions and uses thereof

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Publication number Publication date
KR830005872A (ko) 1983-09-14
JPS57501236A (fr) 1982-07-15
EP0058192A1 (fr) 1982-08-25

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