WO2008135419A2 - Agents anti-il-6 pour améliorer le fonctionnement primaire de greffes allogènes - Google Patents

Agents anti-il-6 pour améliorer le fonctionnement primaire de greffes allogènes Download PDF

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Publication number
WO2008135419A2
WO2008135419A2 PCT/EP2008/055124 EP2008055124W WO2008135419A2 WO 2008135419 A2 WO2008135419 A2 WO 2008135419A2 EP 2008055124 W EP2008055124 W EP 2008055124W WO 2008135419 A2 WO2008135419 A2 WO 2008135419A2
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WO
WIPO (PCT)
Prior art keywords
interleukin
antagonist
organ
graft function
preventing
Prior art date
Application number
PCT/EP2008/055124
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English (en)
Other versions
WO2008135419A3 (fr
Inventor
Birgit Sawitzki
Weihua Gong
Andreas Pascher
Hans-Dieter Volk
Original Assignee
Charité Universitätsmedizin Berlin
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.)
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Publication date
Application filed by Charité Universitätsmedizin Berlin filed Critical Charité Universitätsmedizin Berlin
Publication of WO2008135419A2 publication Critical patent/WO2008135419A2/fr
Publication of WO2008135419A3 publication Critical patent/WO2008135419A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to the use of interleukin-6 antagonists for preventing, treating or ameliorating delayed graft function and/or for improving primary and/or long-term graft function, particularly in kidney transplantation, and corresponding medicaments.
  • delayed graft functioning is a frequently occurring problem. Particularly in the field of kidney transplantation, it is frequently observed that a transplanted organ is not or not sufficiently functioning within the first days after surgery. This results increased serum creatinine concentration and oliguria, necessitating a dialysis treatment of the organ recipient. Approximately 20 to 50 % of all kidney transplantations are plagued by delayed organ function. It is to be noted that the delayed graft function is not to be confused with graft rejection.
  • "delayed graft functioning" is defined as the medical condition after organ transplantation characterized by the absence or incompleteness of the respective organs functions compared to a transplant not suffering from this condition. Particularly, delayed graft function in kidney transplantation is characterized by a lack of decrease in serum creatinine levels compared to the level before surgery. Sometimes, serum creatinine levels even rise post-operatively in delayed graft function.
  • a preventing solution containing a steroid, in particular prednisolone, as the active ingredient may improve primary graft function, in addition to common side effects of steroid treatment excessive cell death in the transplanted organ has been observed (see Fig. 6d), which leads to long-term damages of the transplanted organ and, thus, to a decreased long-term survival.
  • the present invention is based on the unexpected discovery that the administration of an interleukin-6 antagonist prevents or counteracts against delayed graft function and also provides a better long-term survival rate without the common side effects correlated with a steroid treatment in comparison with a treatment with prednisolone (see Example 3).
  • the inventive administration is particularly suitable for preventing or treating delayed graft function in kidney transplantation. Upon administration of an interleukin-6 antagonist functioning of a transplanted kidney could be obtained or restored and maintained over a long-term period (measured by serum creatinine concentration; cf. examples).
  • the invention provides the use of an interleukin-6 antagonist in the preparation of a medicament for preventing, treating or ameliorating delayed graft function.
  • the invention also provides the use of an interleukin-6 antagonist in the preparation of a medicament for improving primary and/or long term graft function.
  • interleukin-6 antagonists had so far only been contemplated in the field of graft rejection (WO 2004/039826).
  • delayed graft functioning is different from graft rejection as indicated above; prophylactic and therapeutic approaches for the prevention of graft rejection are not applicable to the field of preventing, treating or ameliorating delayed graft function.
  • effectiveness of interleukin-6 antagonists for the prevention of graft rejection has so for not been proven but only specu- lated.
  • WO 2004/039826 does not disclose any indication of the interleukin-6 antagonists described therein for the actual therapeutic effectiveness regarding the treatment or prevention of graft rejection.
  • the interleukin-6 antagonist is typically a small molecule and/or a peptide.
  • the interleukin-6 antagonist is a peptide or more preferably a monoclonal and polyclonal anti-interleukin-6 antibody, chimaeric - A -
  • Suitable anti- interleukin-6 antibodies are disclosed, e.g., in WO 2004/03928621.
  • an anti-interleukin-6-receptor antibody that interferes with the receptor's ability to elicit a normal reaction in response to interleukin-6 exposure is also considered an interleukin-6 antagonist.
  • the interleuin-6-antagonist is a small molecule selected from the group consisting of galiellalactone; (+)-madindoline; hydrophobic bile acids, preferably glycochenodeoxycholate; Cyclopentenone; 15-deoxy- Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)); and pyrrolidine dithiocarbamate (PDTC). More preferred are galiellalactone and (+)-madindoline. Galiellalactone inhibits the interleukin-6 signal transduction and (+)-madindoline prevents homodimerization of the interleukin-6 receptor.
  • interleukin-6 antagonists over peptides as interleukin-6 antagonist may be the reduced risk of immunologic reaction in the recipient and better diffusion properties.
  • an interleukin-6 antagonist wherein the interleukin-6 antagonist is according to the invention a peptide, preferably a monoclonal or polyclonal anti-interleukin-6 antibody, chimaeric anti-interleukin-6 antibody and antigen-binding fragment thereof or monoclonal or polyclonal anti- interleukin-6-receptor antibody and antigen-binding fragment thereof or a peptide derived from the acidic domain of gp130, e.g.
  • the interleukin-6 antagonist is a small molecule, preferably a small molecule selected from the group consisting of galiellalactone; (+)-madindoline; hydrophobic bile acids, preferably glycochenodeoxycholate; Cyclopentenone; 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)); and pyrrolidine dithiocarbamate (PDTC) and more preferably galiellalactone and (+)-madindoline in the preparation of a medicament for preventing, treating or ameliorating delayed graft function in renal transplantation.
  • the interleukin-6 antagonist is a small molecule, preferably a small molecule selected from the group consisting of galiellalactone; (+)-madindoline; hydrophobic bile acids, preferably glycochenodeoxycholate; Cyclopentenone; 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)); and
  • the invention also provides an interleukin-6 antagonist according to the invention for use in a method for preventing, treating or ameliorating delayed graft function and/or in a method for improving primary and/or long term graft function, wherein the inter- leukin-6 antagonists is a peptide, preferably monoclonal and polyclonal anti- interleukin-6 antibody, chimaeric anti-interleukin-6 antibody and antigen-binding fragments thereof or monoclonal or polyclonal anti-interleukin-6-receptor antibody and antigen-binding fragments thereof or a peptide derived from the acidic domain of gp130, e.g.
  • the interleukin-6 antagonist is a small molecule, preferably a small molecule selected from the group consisting of galiellalactone; (+)- madindoline; hydrophobic bile acids, preferably glycochenodeoxycholate; Cyclopen- tenone; 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)); and pyrrolidine di- thiocarbamate (PDTC) and more preferably galiellalactone and (+)-madindoline.
  • the interleukin-6 antagonist is a small molecule, preferably a small molecule selected from the group consisting of galiellalactone; (+)- madindoline; hydrophobic bile acids, preferably glycochenodeoxycholate; Cyclopen- tenone; 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)); and pyrrolidine di- thiocarbamate (PDTC) and more
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising, consisting essentially or consisting of an interleukin-6 antagonist as described according to the invention and a pharmaceutical acceptable excipient.
  • the interleukin-6 antagonist can also be formulated or used as a mixture of two or more of such indi- vidual interleukin-6 antagonists.
  • polyclonal antibodies against interleukin-6 and/or its receptor are considered to be "an interleukin-6 antagonist" according to the present invention.
  • a method for preparing a graft organ and particularly a kidney for transplantation comprising or consisting of the following steps:
  • the interleukin-6 antagonist which, as described above, preferably is or comprises an antibody or antigen-binding fragment thereof, is preferably administered outside of the recipient body to the organ, especially the kidney.
  • the method for preparing a graft organ is particularly preferred when comprising or consisting of the following steps:
  • the perfusion solution is a cooled solution used during the cold ischemia time.
  • the effective amount of the interleukin-6 antagonist or a pharmaceutical composition according to the present invention is an amount of the interleukin-6 antagonist, which reduces the activity of interleukin-6 and/or reduces the activity of interleukin-6 receptors.
  • the interleukin-6 antagonist is provided in such an amount that after application all interleukin-6 receptors are blocked.
  • a method of preventing, treating or ameliorating delayed graft function and/or improving primary and/or long term graft functioning in a mammal comprising or consisting of the step of administering to a mammal prior, during and/or after implantation of an organ to be implanted, preferably a kidney, an effective amount of an interleukin-6 antagonist of the present invention.
  • an organ to be implanted preferably a kidney
  • an interleukin-6 antagonist of the present invention is administered to the mammal (recipient) after the implantation of the organ, then the interleukin-6 antagonist is preferably administered until the primary graft function in the recipient is observed.
  • the administration period of the interleukin-6 antagonist of the present invention is dependent on the response of the recipient, which can be measured by the serum creatinine levels and/or the glomuleric filtration rate.
  • the interleukin-6 antagonist is administered / ' . v. , more preferably / ' . v. via Vena portae.
  • Figure 1 a correlation between donor and recipient weight difference and serum creatinine levels
  • Figure 4 serum creatinine levels with low and high weight differences between donor and recipient, and influence of anti-interleukin-6 antibodies on serum creatinine levels.
  • Figure 5 Serum creatinine levels of recipients 24 hours post-transplantation of allogenic kidney grafts comparing anti-IL6 and steroid treatment
  • Figures 6a Histological analysis (H&E) of grafts harvested 24 hours post- b, c and d transplantation of allogenic kidney grafts.
  • Figures 2 and 3 show that in transplantations with a high weight difference between donor and recipient, intragraft interleukin-6 and heme oxygenase 1 levels were in- creased compared to the control group with low weight difference between donor and recipient.
  • Interleukin-6 and heme oxygenase 1 gene expression in grafts from lower-weight donor is 10 times higher than that from little weight difference grafts.
  • Immunohistochemistry analysis revealed a dense staining of heme oxygenase 1 and interleukin-6 in tubular epithelial cells of grafts from lower weight donors (no figures). Immediate post-transplatation targeting of IL-6 receptor with 500 ⁇ g Lv.
  • anti-IL-6-R ⁇ interleukin-6 receptor antagonist
  • interleukin-6 antagonist and in particular interleukin-6 receptor antibody antagonist (anti-IL6R antibody) mediated rescue of primary graft function
  • interleukin-6 receptor antibody antagonist anti-IL6R antibody

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cell Biology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Transplantation (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

La présente invention porte sur l'utilisation d'antagonistes de l'interleukine 6 pour prévenir, traiter ou améliorer une fonction de greffe retardée et/ou pour améliorer une fonction de greffe primaire et/ou à long terme, en particulier dans une transplantation de rein. L'invention porte également sur les médicaments correspondants.
PCT/EP2008/055124 2007-05-04 2008-04-25 Agents anti-il-6 pour améliorer le fonctionnement primaire de greffes allogènes WO2008135419A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US92757007P 2007-05-04 2007-05-04
US60/927,570 2007-05-04

Publications (2)

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WO2008135419A2 true WO2008135419A2 (fr) 2008-11-13
WO2008135419A3 WO2008135419A3 (fr) 2008-12-31

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9150531B2 (en) 2010-07-19 2015-10-06 Glactone Pharma Development Ab Tricyclic lactones for treatment of cancer

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004039826A1 (fr) * 2001-11-14 2004-05-13 Centocor, Inc. Anticorps anti-il-6, compositions, methodes et utilisations associees
WO2007043641A1 (fr) * 2005-10-14 2007-04-19 Fukuoka University Inhibiteur de dysfonctionnement d'îlots transplantés dans un transplant d'îlots

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004039826A1 (fr) * 2001-11-14 2004-05-13 Centocor, Inc. Anticorps anti-il-6, compositions, methodes et utilisations associees
WO2007043641A1 (fr) * 2005-10-14 2007-04-19 Fukuoka University Inhibiteur de dysfonctionnement d'îlots transplantés dans un transplant d'îlots

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LUDWIN D ET AL: "The relationship between cadaver donor interleukin 6 levels and delayed graft function in kidney transplantation." TRANSPLANTATION JAN 1992, vol. 53, no. 1, January 1992 (1992-01), pages 222-223, XP002490599 ISSN: 0041-1337 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9150531B2 (en) 2010-07-19 2015-10-06 Glactone Pharma Development Ab Tricyclic lactones for treatment of cancer

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