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WO1990001328A1 - Fnt et ses compositions dans le traitement ou la prophylaxie de l'hepatite b - Google Patents

Fnt et ses compositions dans le traitement ou la prophylaxie de l'hepatite b Download PDF

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Publication number
WO1990001328A1
WO1990001328A1 PCT/GB1989/000897 GB8900897W WO9001328A1 WO 1990001328 A1 WO1990001328 A1 WO 1990001328A1 GB 8900897 W GB8900897 W GB 8900897W WO 9001328 A1 WO9001328 A1 WO 9001328A1
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WO
WIPO (PCT)
Prior art keywords
tnf
formulation
hepatitis
treatment
human
Prior art date
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Ceased
Application number
PCT/GB1989/000897
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English (en)
Inventor
Roger Samuel Williams
Graeme James Mackay Alexander
Christopher R. Franks
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Individual
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Individual
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Filing date
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Application filed by Individual filed Critical Individual
Publication of WO1990001328A1 publication Critical patent/WO1990001328A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • A61K38/191—Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta

Definitions

  • This invention relates to TNF and formulations thereof in the treatment or prophylaxis of hepatitis B.
  • the invention also includes a method of making a medicament and methods for the treatment or prophylaxis of hepatitis B in mammalian hosts.
  • the TNF is recombinant TNF (rTNF) purified to homogeneity.
  • Hepatitis B virus infection often leads to chronic persistent hepatitis, chronic active hepatitis or cirrhosis, potential hepatic failure, or hepatocellular carcinoma (HCC) (Annals of Intern Med 101: 613-616) . The latter two conditions are associated with a significant 5 year mortality (15% and 45%, respectively) .
  • liver dysfunction such as bleeding disorders, ascites, and hepatic encephalopathy
  • the biochemical abnormalities usually include an elevation of liver enzymes in the serum (serum glutamic oxaloacetate transaminase and serum glutamic pyruvic transaminase) . These tend to be more marked in patients with chronic active hepatitis. Reduction in serum albumin, elevation of serum bilirubin and a prolongation of prothrombin time occur as late manifestations of chronic active hepatitis or due to the development of cirrhosis.
  • HBsAg Hepatitis Be antigen
  • Tumour necrosis factor is a macrophage derived cytokine which has an antitumour cytotoxic activity and a regulatory activity on the cell-interactions (Proc. Natl. Acad. Sci, USA, 72: 3666-3670; BR. J. Cancer 38: 310-315; Science 230: 630-632).
  • Production of oxygen radicals by activated PMN's could be one of the tumoricidal effector mechanisms.
  • TNF exerts immunoregulatory activity by enhancing the proliferative capacity of activated T-lympho ⁇ ytes via enhancement of high affinity IL-2 receptor expression (Cell. Immunol. 100: 260-267) and stimulates, together with IL-2, IFN-gam a production. IFN-gamma in turn, activates neutrophils, eosinophils and macrophage functions including TNF production (New
  • TNF can exert either direct or indirect antiviral activity for both RNA and DNA viruses (Cancer research 47, June 1, 2793-2798; Nature 323: 816-822), and acts as a growth stimulating factor for diploid fibroblats (Br. J. Cancer 38: 310-315).
  • TNF interferes with normal hematopoiesis as revealed by strong inhibition of in vitro colony forming units (Proc. Natl. Acad. Sci. USA 83: 446-450).
  • TNF may mediate endotoxin shock (J. Immunol. 136: 4487-4495) .
  • Tumour necrosis factor produced by activated cells of the monocyte/macrophage lineage, was first demonstrated to cause hemorrhagic necrosis of murine, simian, and human tumours and tumour cell lines (Hepatolo ⁇ y 2: 39-49; Proc. Natl. Acad. Sci, USA, 72: 3666-3670; Br. J. Cancer 38: 310-315; Science 230: 630-632) .
  • Evidence now shows that in addition to cytotoxic activity against virally infected or tumour cells, the monokine has, in concert with interleukin-2 and gamma-interferon important autocrine regulatory effects on normal cells as well.
  • TNF was shown to affect T-lymphocyte differentiation via enhancement of high affinity IL-2 receptor expression (Cell. Immunol. 100: 260-267), acts as a growth stimulating factor for diploid fibroblasts, enhances functional activity of neutrophils and eosinophils (J. Immunol. 138 (in press); J. Immunol., 135: 2069-2073), and adherence to endothelial cells (Proc. Natl. Acad. Sci. USA, 82: 1055-1059) , induces granulocyte/monocyte colony stimulating factor (GM-CSF) production by various cell types (Proc. Nat. Acad. Sci. USA 82: 8667-8671) and enhances HLA expression in various tissues
  • GM-CSF granulocyte/monocyte colony stimulating factor
  • TNF interferes with normal hematopoiesis (Proc. Natl. Acad. Sci. USA 83: 446-450) and may be a mediator in cachexia and entotoxin shock (J. Immunol. 136: 4487-4495).
  • IFN-gamma acts synergistically with TNF to increase target cell susceptibility, and to activate macrophage functions including TNF production (New Engl. J. Med. 316: 379-385) .
  • TNF synergy with interferons was also demonstrated in direct or indirect activity against both DNA and RNA viruses (Cancer research 47, June 1, 2793-2798; Nature 323: 816-822; Nature 323: 819-822) via inhibition of viral replication and/or stimulation of T-lymphocytes to produce IL-2 and TNF, and/or induction of superoxide production and cytotoxicity of neutrophils.
  • TNF as such in the treatment of hepatitis B.
  • tumour necrosis factor production was extensive.
  • TNF hepatitis B
  • the present invention is directed to a method for the treatment or prophylaxis of hepatitis B in mammals comprising administering, before or after infection of the host, an effective amount of tumour necrosis factor (TNF) from a mammalian species.
  • TNF tumour necrosis factor
  • Recombinant TNF is preferred, and the mammal may be a human.
  • a pharmaceutical or veterinary formulation comprising an effective amount of TNF formulated for use in the treatment or prophylaxis of hepatitis B;
  • a pharmaceutical or veterinary formulation comprising TNF which has passed the USP sterility, rabbit pyrogen and general safety tests and has an activity greater than 5 x 10 ⁇ units/ g and is formulated for use in the treatment or prophylaxis of hepatitis B;
  • TNF for use in the treatment or prophylaxis of hepatitis B.
  • the term "recombinant TNF” refers to TNF produced by recombinant DNA techniques wherein generally the gene coding for the TNF is cloned by known recombinant DNA technology.
  • a suitable DNA vector such as a bacterial plasmid, preferably an . coli plasmid, to obtain a recombinant plasmid, and the plasmid is used to transform a suitable host.
  • the gene is expressed in the host to produce the recombinant TNF protein.
  • Suitable recombinant plasmids for this purpose include pBR322, pCRl, pMB9 and pSCl. All of these are publicly available.
  • the transformed host may be eucaryotic or procaryoti ⁇ , preferably a pro ⁇ aryotic host.
  • the term “pharmaceutically or veterinarily acceptable” refers to absence of interference with the effectiveness of the biological activity of the active ingredient and absence of toxicity to the patient.
  • the method of this invention involves administering to a mammal, preferably a human, an effective amount of TNF.
  • the administration(s) may take place by any suitable technique, preferably parenteral administration.
  • parenteral administration include intravenous, intraarterial, intramuscular, and intraperitoneal, with intravenous being preferred.
  • the dose and dosage regimen will depend mainly on whether the TNF is being administered for therapeutic or prophylactic purposes, the stage and degree of infection, the patient, and the patient's history.
  • the amount should ideally be effective to achieve a protection level of at least 50%, preferably at least 70%; dosages which do not achieve this minimal level of effectiveness should not usually be employed.
  • the doses may be single doses, multiple doses over a period of several days or repeated cycles of multiple doses over a period of several days followed by several days of no administration.
  • a protection level of at least 50% means that at least 50% of the treated hosts exhibit improvement against the infection, including but not limited to improved survival rate, more rapid recovery, or improvements or elimination of symptoms including inter alia clearing transiently, or permanently, markers of hepatitis B virus replication.
  • the TNF will generally be formulated in a unit dosage injectable form (solution, suspension, emulsion) , preferably in a pharmaceutically or veterinarily acceptable carrier medium that is inherently non-toxic and non-therapeutic or non-prophylactic.
  • a pharmaceutically or veterinarily acceptable carrier medium that is inherently non-toxic and non-therapeutic or non-prophylactic.
  • examples of such vehicles include saline. Ringer's solution, dextrose solution, mannitol, and normal serum albumin. Non-aqueous vehicles such as fixed oils and ethyl oleate may also be used.
  • the carrier medium may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability, e.g., buffers and preservatives.
  • the TNF will typically be formulated in such carriers at a concentration of about 0.1 mg/ml to 100 mg/ml.
  • the TNF employed herein may be obtained from tissue cultures or by recombinant techniques, and from any mammalian source such as, e.g., mouse, rat, rabbit, primate, pig, and humans.
  • the TNF is derived from a human source, and more preferably is a human recombinant TNF.
  • Recombinant human TNF may be obtained as described by Pennica et al., Nature, 312:724-729 (1984); Yamada et al. , J. Biotechnology. (1985) 2:141-153; Wang et al.. Science (1985), 228.:149-154; EP 155,549 published September 29, 1985, EP 158,286 published October 16, 1985; EP 168,214 published January 15, 1986; and PCT US85/01921 published April, 1986.
  • the recombinant rabbit TNF may be obtained as described in EP 146,026 published June 26, 1985 and EP 148,311 published July 17, 1985.
  • the TNF is a human TNF mutein that is N-terminally deleted, preferably wherein the first eight amino acid residues have been deleted, using the procedure described in U.S. Patent No. 4,677,063 issued June 30, 1987 or the TNF is a cysteine-depleted mutein described in U.S. Serial No. 698,939 filed February 7, 1985 and in U.S. Patent No. 4,518,584, supra (for IL-2 but applicable to TNF) .
  • the TNF should normally be of sufficient purity that it passes the USP sterility test, the rabbit pyrogen test and general safety tests and in addition should preferably have an activity of greater than 5 x 10 6 units/mg TNF.
  • TNF for use in the present methods can be provided in vials kept at a temperature of at least -20°C.
  • the TNF should be allowed to thaw at room temperature prior to use.
  • the vials should not be shaken.
  • Thawed solutions may be refrozen once but it is preferable that the solution once thawed be used within three hours due to sterility considerations.
  • Each vial can contain, for example approximately 0.3 g TNF in 1.2 ml of solution giving an approximate TNF concentration of 0.25 mg/ml.
  • the solution may also contain suitable pharmaceutically or veterinarily acceptable carriers and/or stabilisers, e.g. 1% annitol, the whole being dissolved in a suitable buffer, e.g. sodium phosphate buffer having a pH between 7.2 and 7.8.
  • the TNF is preferably adminstered in a solution containing serum albumin, e.g. 0.25% serum albumin. This prevents adherence of TNF to the walls of bottles and tubing etc.
  • serum albumin e.g. 0.25% serum albumin.
  • One method of producing the solution is to add a specified dose of TNF to 100 ml of sodium chloride injection which also contains the specified percentage of normal serum albumin (Human, USP) .
  • Each patient is subject to a treatment cycle consisting of the administration of a specified dose of TNF on a daily basis for five days followed by 3 doses/week for a further three weeks.
  • a treatment cycle consisting of the administration of a specified dose of TNF on a daily basis for five days followed by 3 doses/week for a further three weeks.
  • an intramuscular injection of TNF daily at a dose of 10-100 g/m 2 /day followed by 3 doses of 10-100 ⁇ g/m 2 / da y f° r a further three weeks.
  • the patient's response measured as the presence or absence of the infection, can be evaluated.
  • the treatment cycle can be repeated. Up to 4 cycles of treatment, can be given. Continuation of the treatment beyond 4 cycles for a subject showing a complete or partial response to the treatment should be at the discretion of- the treatment supervisor.
  • Suitable daily doses of TNF are 10, 15, 30, 60, 80 or 100 ⁇ g/m 2 /day.
  • Each patient is subject to a treatment cycle consisting of the administration of a specified dose of TNF on a daily basis for five days. For example a 15 minute i.v. infusion of TNF daily, at a dose of 30-250 / _.g/m 2 /day followed by 10 days of rest, i.e. no administration of TNF. At the end of each rest period the patient's response, measured as the presence or absence of the infection, can be evaluated.
  • the treatment cycle can be repeated. Up to 10 cycles of treatment, can be given. Continuation of the treatment beyond 10 cycles for a subject showing a complete or partial response to the treatment should be at the discretion of the treatment supervisor.
  • Suitable daily dosages of TNF are 30, 40, 70, 110, 180 or 250 ⁇ g/m 2 /day.

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

Abstract

Un médicament pour le traitement de l'hépatite B chez des mammifères comprenant le FNT (facteur de nécrose tumorale), ainsi que des procédés d'administration d'un tel médicament.
PCT/GB1989/000897 1988-08-04 1989-08-04 Fnt et ses compositions dans le traitement ou la prophylaxie de l'hepatite b Ceased WO1990001328A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8818567.3 1988-08-04
GB8818567A GB2221619A (en) 1988-08-04 1988-08-04 Tnf in the treatment of hepatitis b

Publications (1)

Publication Number Publication Date
WO1990001328A1 true WO1990001328A1 (fr) 1990-02-22

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Application Number Title Priority Date Filing Date
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GB (1) GB2221619A (fr)
WO (1) WO1990001328A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5717741A (en) * 1992-08-26 1998-02-10 Bellsouth Corp. Method for handling telephonic messages

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3525750A1 (de) * 1985-07-19 1987-01-29 Basf Ag Verwendung von tnp zur herstellung von arzneimitteln

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
Baillieres Clin. Gastroenterol., Vol. 3, No. 1, January 1989 G. Alexander: "Treatment of Acute and Chronic Viral Hepatitis" pages 1-20 *
British Medical Journal, Vol. 292, No. 6525, 5 April 1986, British Medical Journal, (London, GB) G. ALEXANDER et al.: "Antiviral Treatment in Chronic Infection with Hepatitus B Virus", pages 915-917 *
Gastroenterology, Vol. 92 (5 Part 2) May 1987 R. HERRMANN et al.: "Normal Tumor Necrosis Factor in Alcoholic Hepatitis" page 1795 *
Hepatology, Vol. 8, No. 5, November 1988, F.LARRAS et al.: "Tumor Necrosis Factor in Chronic Hepatitus B", see Abstract 267 *
Medical Hypotheses, Vol. 27, No. 3, 1988 Longman Group UK Ltd (GB) D. ADERKA et al.: "Does Tumor Necrosis Factor Play a Role in the Pathogenesis of Fulminant Hepatitis? pages 193-196 *
Nature, Vol. 323, 30 October 1986, G.H.W. WONG et al.: "Tomour Necrosis Factors alpha and beta Inhibit Virus Replication and Synergize with Interferons", pages 819-822 *
The Lancet, Vol. 2, No. 8602, 9 July 1988 Y. MUTO et al.: "Enhanced Tumour Necrosis Factor and Interleukin-1 in Fulminant Hepatic Failure", pages 72-74 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5717741A (en) * 1992-08-26 1998-02-10 Bellsouth Corp. Method for handling telephonic messages
US5764747A (en) * 1992-08-26 1998-06-09 Bellsouth Corporation Personal number communication system
US5857013A (en) * 1992-08-26 1999-01-05 Bellsouth Corporation Method for automatically returning voice mail messages

Also Published As

Publication number Publication date
GB8818567D0 (en) 1988-09-07
GB2221619A (en) 1990-02-14

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