WO1996005852A1 - Traitement des maladies inflammatoires des voies gastro-intestinales - Google Patents
Traitement des maladies inflammatoires des voies gastro-intestinales Download PDFInfo
- 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
Links
- 210000001035 gastrointestinal tract Anatomy 0.000 title claims abstract description 11
- 208000027866 inflammatory disease Diseases 0.000 title claims abstract description 11
- 125000000539 amino acid group Chemical group 0.000 claims abstract description 45
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 34
- 239000003814 drug Substances 0.000 claims abstract description 12
- 239000003446 ligand Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 11
- 208000011231 Crohn disease Diseases 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 230000007935 neutral effect Effects 0.000 claims abstract description 8
- 235000001014 amino acid Nutrition 0.000 claims abstract description 7
- 150000001413 amino acids Chemical class 0.000 claims abstract description 7
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims abstract description 6
- 125000006850 spacer group Chemical group 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims abstract description 4
- 239000002753 trypsin inhibitor Substances 0.000 claims description 4
- 230000000890 antigenic effect Effects 0.000 claims description 3
- 210000004899 c-terminal region Anatomy 0.000 claims 2
- 101710081722 Antitrypsin Proteins 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 230000001475 anti-trypsic effect Effects 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 8
- 206010009900 Colitis ulcerative Diseases 0.000 abstract description 7
- 201000006704 Ulcerative Colitis Diseases 0.000 abstract description 7
- 201000010099 disease Diseases 0.000 abstract description 7
- 208000015943 Coeliac disease Diseases 0.000 abstract description 5
- 239000003085 diluting agent Substances 0.000 abstract description 3
- KGIHMGPYGXBYJJ-SRVKXCTJSA-N Cys-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CS KGIHMGPYGXBYJJ-SRVKXCTJSA-N 0.000 abstract 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 9
- 210000002966 serum Anatomy 0.000 description 9
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 206010003267 Arthritis reactive Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 206010008399 Change of bowel habit Diseases 0.000 description 1
- 150000008574 D-amino acids Chemical class 0.000 description 1
- 206010012468 Dermatitis herpetiformis Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- QSLKWWDKIXMWJV-SRVKXCTJSA-N His-Cys-Lys Chemical compound C1=C(NC=N1)C[C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCCN)C(=O)O)N QSLKWWDKIXMWJV-SRVKXCTJSA-N 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 235000006171 gluten free diet Nutrition 0.000 description 1
- 235000020884 gluten-free diet Nutrition 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000003870 intestinal permeability Effects 0.000 description 1
- 108010054155 lysyllysine Proteins 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 208000002574 reactive arthritis Diseases 0.000 description 1
- 239000000126 substance Chemical group 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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.
Landscapes
- 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)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Zoology (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.
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 |
|---|---|---|---|
| GB9416865A GB9416865D0 (en) | 1994-08-19 | 1994-08-19 | Treatment of inflammatory diseases of the gastro-intestinal tract |
| GB9416865.5 | 1994-08-19 |
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 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)
| 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 |
-
1994
- 1994-08-19 GB GB9416865A patent/GB9416865D0/en active Pending
-
1995
- 1995-08-14 AU AU32275/95A patent/AU3227595A/en not_active Abandoned
- 1995-08-14 WO PCT/GB1995/001913 patent/WO1996005852A1/fr active Application Filing
Patent Citations (2)
| 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)
| 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 |
|---|---|
| GB9416865D0 (en) | 1994-10-12 |
| AU3227595A (en) | 1996-03-14 |
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