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WO1996005852A1 - Traitement des maladies inflammatoires des voies gastro-intestinales - Google Patents

Traitement des maladies inflammatoires des voies gastro-intestinales Download PDF

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Publication number
WO1996005852A1
WO1996005852A1 PCT/GB1995/001913 GB9501913W WO9605852A1 WO 1996005852 A1 WO1996005852 A1 WO 1996005852A1 GB 9501913 W GB9501913 W GB 9501913W WO 9605852 A1 WO9605852 A1 WO 9605852A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino acid
positively charged
peptide
acid residues
treatment
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.)
Ceased
Application number
PCT/GB1995/001913
Other languages
English (en)
Inventor
Denis Raymond Stanworth
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.)
Sanofi Pasteur Holding Ltd
Original Assignee
Peptide Therapeutics Ltd
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 Peptide Therapeutics Ltd filed Critical Peptide Therapeutics Ltd
Priority to AU32275/95A priority Critical patent/AU3227595A/en
Publication of WO1996005852A1 publication Critical patent/WO1996005852A1/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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • 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
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins

Definitions

  • the present invention relates to use of a peptide or ligand in the manufacture of a medicament for the treatment of certain inflammatory diseases of the gastro-intestinal tract, such as coeliac disease, Crohn's disease, ulcerative colitis etc., and a method of treatment of the diseases comprising administering an effective dose of a medicament comprising the peptide or ligand.
  • Amino acids and amino acid residues are represented herein by their standard codes as identified by IUPAC-IUB Biochemical Nomenclature Commission and represent D and L amino acids, their analogues or derivatives.
  • inflammatory diseases of the gastro- intestinal tract such as inflammatory reactions in the bowel are usually insidious in onset and may vary according to the area of the bowel affection.
  • a change in bowel habit e.g. diarrhoea or stearrhoea is a finding common to many gastro- intestinal syndromes. This may be accompanied by chronic abdominal pain, fever or anaemia.
  • RA articular inflammatory disease rheumatoid arthritis
  • the major pathological factor in RA is believed by Stanworth to be a covalently linked complex of serum IgA and ⁇ 2 -antitrypsin (cxjA ) , a major anti-protease.
  • This disulphide-bridged complex is found to be present at abnormally high levels in the sera and joint fluids of RA patients and the complex has potent cytotoxicity.
  • IDGIT inflammatory diseases of the gastro- intestinal tract
  • the present invention provides use of a peptide or ligand in the manufacture of a medicament for the treatment of certain IDGIT, such as coeliac disease, Crohn's disease, ulcerative colitis etc., and a method of treatment of the diseases comprising administering an effective dose of a medicament comprising the peptide or ligand.
  • the present peptide has not more than 20 amino acid residues, and comprises a thiol-active cysteine residue and at least two positively charged amino acid residues situated at, adjacent or near to the N terminus or at, adjacent or near to the C terminus or at, adjacent or near to both termini; or this peptide and a pharmaceutically acceptable diluent or carrier.
  • the positively charged amino acid residues are separated from the thiol-active cysteine residue by a spacer, for example an amino acid residue sequence, a hydrocarbon chain or a chemical bond.
  • the spacer comprises 1-4 preferably neutrally charged amino acid residues.
  • the neutrally charged amino acid residues are glycine.
  • the peptide or analog comprises 3-20 amino acid residues; more preferably 4-10.
  • the peptide or analog comprises amino acid residues having a sequence selected from the group which comprises:
  • the C terminus of the peptide or analog is amidated to prolong its half life, thus enabling a shorter peptide to be used.
  • the invention can provide a method of treatment of IDGIT comprising administering an effective dose of a peptide or analogue thereof having the following general formula:
  • the present invention can provide a method of treatment of IDGIT comprising administering an effective dose of a ligand comprising an antibody domain which can bind specifically to an antigenic determinant specific to a complex of human IgA and Oi-antitrypsin; or this ligand and a pharmaceutically acceptable diluent or carrier.
  • the antibody can be monoclonal or polyclonal or can comprise a fragment thereof; preferably it is humanised for example using the technique described in EP-0 239 400 (Winter) .
  • the present invention can provide a use of the peptide or ligand described herein in the manufacture of a medicament for the treatment of IDGIT.
  • Peptides for use according to the present invention were prepared using standard Fmoc chemistry as described in WO 93/11153 (Stanworth et al) .
  • Figure 1 shows serum IgA- jAT values in patients with Crohns disease
  • FIG. 1 shows serum IgA-otjAT values in patients with Ulcerative Colitis
  • Figure 3 shows serum IgA-c ⁇ AT values in Chronic Intestinal and Cutaneous Inflammation.
  • the first bar shows a total for all patients with Crohns disease.
  • the second and third bars distinguish the serum IgA- ⁇ AT values in the small bowel and large bowel indicating significantly raised levels in the small bowel.
  • the remaining three bars show the serum IgA-c ⁇ AT values distinguished according to the grade or severity of the disease in the patient : grade 3 being the most severe and also showing the highest level of IgA-oijAT.
  • the first bar shows a value for all patients with Ulcerative Colitis and the remaining four bars showing the increase of serum IgA- ⁇ jAT value with increasing grade or severity of the disease.
  • Figure 3 the first three bars compare a control with patients having Crohns disease or Ulcerative Colitis. The next bar shows the level of serum IgA- ⁇ jAT in patients with untreated coeliac disease and also the level in patients treated with a gluten- free diet. The final two bars show, by comparison, serum IgA- ctiAT values in untreated and treated patients having dermatitis herpetiformis.

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

Abstract

La présente invention concerne l'emploi d'un peptide ou d'un ligand dans la production d'un médicament utilisé pour traiter certaines maladies inflammatoires des voies gastro-intestinales, comme la maladie coeliaque, la maladie de Crohn, la rectocolite hémorragique etc., et une méthode de traitement consistant à administrer une dose efficace d'un médicament contenant le peptide ou le ligand en question. Ce peptide, qui est composé de restes aminoacides dont le nombre n'excède pas vingt, comporte un reste de cystéine à activité thiol ainsi que d'au moins deux restes aminoacides chargés positivement localisés sur l'extrémité terminale N, attenants à N ou proches de N, ou bien localisés sur l'extrémité terminale C, attenants à C ou proches de C, ou encore localisés sur les deux extrémités terminales, attenants ou proches de celles-ci; ou ce peptide et un diluant ou un porteur acceptable du point de vue pharmaceutique. Ce peptide ou l'analogue comporte des restes aminoacides ayant une séquence tirée du groupe comprenant: Cys-Lys-Lys; His-Cys-Lys-Lys (SEQ ID NO:1). Cette invention peut également concerner une méthode de traitement des maladies inflammatoires des voies gastro-intestinales consistant à administrer une dose efficace d'un médicament contenant le peptide ou son analogue ayant la formule générale (I) dans laquelle m vaut 0 ou 1, n vaut 0 ou 1 et m + n vaut 1 ou 2; J1 et J2 représentent des séquences de restes aminoacides chargés positivement; Z?1, Z2, B1 et B2¿ représentent des séquences de restes aminoacides neutres ou chargés positivement ou négativement, ou bien toute autre séquence de mélange de restes aminoacides neutres ou chargés positivement ou négativement; x = 0 ou 1, y = 0 ou 1 et x + y = 1 ou 2; c = de 0 à 4, d = de 0 à 4, a = de 0 à 18 et b = de 0 à 18, sous réserve que, quand m = 0, l'un au moins de B2 ou de Z2 soit un reste aminoacide chargé positivement, que, quand n est 0, l'un au moins de B1 ou de Z2 soit un reste aminoacide chargé positivement, que, quand m = n = 1 et que y vaut 0, l'un au moins de Z?1, B1 B2 ou Z2¿ soit un reste aminoacide chargé positivement et enfin que, quand m = n = 1 et que x = 0, l'un au moins de Z?1, B1, B2 ou Z2¿ soit un reste aminoacide chargé positivement: B1 et B2 pouvant également représenter un bras de non-peptide d'une longueur équivalente à celle qui est déterminée par la longueur des restes b et c aminoacides.
PCT/GB1995/001913 1994-08-19 1995-08-14 Traitement des maladies inflammatoires des voies gastro-intestinales Ceased WO1996005852A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU32275/95A AU3227595A (en) 1994-08-19 1995-08-14 Treatment of inflammatory diseases of the gastro-intestinal tract

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9416865.5 1994-08-19
GB9416865A GB9416865D0 (en) 1994-08-19 1994-08-19 Treatment of inflammatory diseases of the gastro-intestinal tract

Publications (1)

Publication Number Publication Date
WO1996005852A1 true WO1996005852A1 (fr) 1996-02-29

Family

ID=10760156

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1995/001913 Ceased WO1996005852A1 (fr) 1994-08-19 1995-08-14 Traitement des maladies inflammatoires des voies gastro-intestinales

Country Status (3)

Country Link
AU (1) AU3227595A (fr)
GB (1) GB9416865D0 (fr)
WO (1) WO1996005852A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991019001A1 (fr) * 1990-05-25 1991-12-12 British Technology Group Ltd Diagnostic immunologique de la polyarthrite rhumatoide
WO1993011153A1 (fr) * 1991-11-25 1993-06-10 Peptide Therapeutics Limited Peptides et anticorps utilises dans le traitement de la polyarthrite rhumatoide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991019001A1 (fr) * 1990-05-25 1991-12-12 British Technology Group Ltd Diagnostic immunologique de la polyarthrite rhumatoide
WO1993011153A1 (fr) * 1991-11-25 1993-06-10 Peptide Therapeutics Limited Peptides et anticorps utilises dans le traitement de la polyarthrite rhumatoide

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HUNDEGGER, K. ET AL: "Enteric protein loss as a marker of intestinal inflammatory activity in Crohn's disease. Comparability of intestinal clearance and stool concentration of alpha-1- antitrypsin ?", Z. GASTROENTEROL. (1992), 30(10), 722-8 *
MATTEY D.L. ET AL.: "IgA alpha1-antitrypsin complex in mesangium, serum and urine of patients with IgA nephropathy", NEPHROLOGY DIALYSIS TRANSPLANTATION, vol. 8, no. 12, OXFORD, pages 1422 *
WARDLE T D ET AL: "IS IMMUNOGLOBULIN A-ALPHA-1 ANTITRYPSIN COMPLEX PATHOGENIC OR A MARK OF DISEASE ACTIVITY IN PATIENTS WITH CHRONIC INTESTINAL INFLAMMATION ?.", 94TH ANNUAL MEETING OF THE AMERICAN GASTROENTEROLOGICAL ASSOCIATION, BOSTON, MASSACHUSETTS, USA, MAY 15-21, 1993. GASTROENTEROLOGY 104 (4 SUPPL.). 1993. A798. *

Also Published As

Publication number Publication date
AU3227595A (en) 1996-03-14
GB9416865D0 (en) 1994-10-12

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