EP1268554A2 - Medicament et moyen diagnostique pour analyser le proteome de surface de cellules tumorales et inflammatoires, et pour traiter des maladies tumorales et inflammatoires, de preference au moyen d'une analyse specifique des recepteurs de chimiokines et de l'interaction de ligands recepteurs de chimioki - Google Patents

Medicament et moyen diagnostique pour analyser le proteome de surface de cellules tumorales et inflammatoires, et pour traiter des maladies tumorales et inflammatoires, de preference au moyen d'une analyse specifique des recepteurs de chimiokines et de l'interaction de ligands recepteurs de chimioki

Info

Publication number
EP1268554A2
EP1268554A2 EP01923710A EP01923710A EP1268554A2 EP 1268554 A2 EP1268554 A2 EP 1268554A2 EP 01923710 A EP01923710 A EP 01923710A EP 01923710 A EP01923710 A EP 01923710A EP 1268554 A2 EP1268554 A2 EP 1268554A2
Authority
EP
European Patent Office
Prior art keywords
chemokine receptor
receptors
chemokine
antibodies
different
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.)
Withdrawn
Application number
EP01923710A
Other languages
German (de)
English (en)
Inventor
Wolf-Georg Forssmann
Knut Adermann
Aleksandra Heitland
Nikolaj Spodsberg
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.)
IPF Pharmaceuticals GmbH
Original Assignee
IPF Pharmaceuticals GmbH
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 IPF Pharmaceuticals GmbH filed Critical IPF Pharmaceuticals GmbH
Publication of EP1268554A2 publication Critical patent/EP1268554A2/fr
Withdrawn legal-status Critical Current

Links

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
    • C07K14/521—Chemokines
    • C07K14/522—Alpha-chemokines, e.g. NAP-2, ENA-78, GRO-alpha/MGSA/NAP-3, GRO-beta/MIP-2alpha, GRO-gamma/MIP-2beta, IP-10, GCP-2, MIG, PBSF, PF-4, KC
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to the preparation of a medicament and a diagnostic agent obtained via a proteome analysis, preferably containing at least two different chemokine receptor ligands or chemokine receptor antibodies, and furthermore the use of at least two different chemokine receptor ligands, chemokine receptor antibodies and / or two different chemokine receptors.
  • the medicament consists in the use of inhibitors, ligands or antibodies of at least two chemokine receptors or the associated algorithms of the surface chemokine receptor proteome as well as the use of at least one chemokine receptor ligand and / or a chemokine receptor, peptides and antibodies and their use for the diagnosis and therapy of tumor diseases and inflammatory diseases.
  • clusters of analyzed tumor cell surface proteomes such as ectoproteases, adhesion molecules or various types of receptors can be used.
  • chemokines of the CC and the CXC chemokines include in particular the chemokines of the CC and the CXC chemokines, preferably, for example, HCC-1 to HCC-3 and SDF-1 (Schulz-Knappe P et al., J Exp ed 183: 295, 1996; Pardigol A et al., Proc Natl Acad Sei USA 95: 6308, 1998; Nagasawa T et al., Proc Natl Acad Sei USA 91: 2305, 1994).
  • MCP-1 and RANTES Wang JM et al., Int J Cancer 75: 900, 1998.
  • tumor cell lines can thus react to specific chemokines by stimulating the receptors. If the corresponding chemokine peptide is formed in corresponding cells, tissues and organs, an autocrine, paracrine or endocrine reaction can occur, whereby cell migration and cell proliferation are influenced. For example, kidney metastases from tumors that have receptors for MCP-1 and RANTES are said to arise preferentially, since a strong expression of these chemokines is observed in the kidney (Wang JM et al., Int J Cancer 75: 900, 1998).
  • chemokines inhibit tumor growth (Wang JM et al., J Interferon Cytokine Res 16: 53, 1996), so that tumor growth can also be negatively influenced by chemokine administration.
  • the role of chemokines in the migration of tumor cells has been observed using breast cancer cell lines (Youngs et al., Int J Cancer 71: 257, 1997).
  • the control of angiogenesis is also influenced positively or negatively by various cytokines.
  • the chemokine receptor CXCR4 via which the chemokine SDF-1 exerts its action, is essential for the vascularization of the gastrointestinal tract (Tachibana K et al., Nature 393: 591, 1998).
  • a technical problem on which the invention is based is the improvement of the diagnosis of tumors and the presence of inflammatory processes.
  • Another problem is the improved treatment of tumors and inflammatory diseases.
  • the problem is solved by a diagnostic agent and a medicament according to the invention.
  • the diagnostic agent according to the invention contains at least two different ligands of receptors which are involved in a disease process.
  • the diagnostic agent according to the invention preferably contains at least two different chemokine receptor ligands, such as protein peptide structures, which interact with chemokine receptors (or other tumor cell surface proteins), namely chemokine receptor ligands, chemokine receptor antagonists and / or chemokine receptor antibodies.
  • the chemokine receptor ligands are preferably chemokines, chemokine derivatives, agonists or antagonists of chemokine receptors, antibodies or antibody fragments which at least partially block the binding site of the chemokine receptor and surprisingly result in inhibition of tumor growth.
  • Chemokines are particularly preferably selected from the group consisting of the natural chemokines C, CC, CXC, CX 3 C, their analogs, binding proteins and antibodies which bind to the specific receptors in accordance with the chemokines mentioned.
  • the chemokine receptors as a whole Crystalproteom and corresponding thereto chemokine receptor ligand in primary and secondary tumors, and circulating single cells are preferably (1) by immunochemical methods (immunohistochemistry using Se ⁇ ensburgen or multiple successive or simultaneous individual cuts, FACS analysis') and additionally (2), or alternatively, the expression at the transcription level is recorded and analyzed by molecular biological methods (PCR or Northern analysis, in-situ hybridization). Clusters of analyzed tumor cell surface proteomes such as ectoproteases, adhesion molecules or various types of receptors can also be used according to the invention.
  • the method according to the invention for the detection of receptors involved in disease processes is closely related to the diagnostic agent according to the invention, expression profiles at the proteome level being examined by means of cell biological or cytochemical methods, in particular by immunochemical methods, immunohistochemistry using serial sections or multiple successive or simultaneous single sections, FACS analysis and / or the expression of receptors at the transcription level by molecular biological methods, in particular PCR, Northern analysis and / or in-situ hybridization processes.
  • the present invention thus also relates to the use of at least two different chemokine receptor ligands and / or two different chemokine receptors for the diagnostic characterization of tumors, which is different for each type of tumor and each individual tumor.
  • the method according to the invention can be used for tumors which originate from the group consisting of colorectal tumors and prostate tumors.
  • tumors of other organ systems can also be addressed diagnostically and thus therapeutically using the method according to the invention.
  • the at least two different chemokine receptors and / or two different chemokine receptor ligands can be used to diagnose inflammatory processes such as organ rejection reactions and to diagnose autoimmune diseases.
  • tumors, inflammatory diseases and autoimmune diseases of the blood system, the lymphatic system, the cardiovascular system, the nervous system, the respiratory tract, the digestive tract, the endocrine system, the skin including the appendages, the musculoskeletal system and the urogenital tract including the kidney can be diagnosed.
  • the diagnostic agent according to the invention enables an expansion of the cytological characterization of tumor tissues compared to conventional diagnostic methods, which after diagnosis can also be used to develop a specific therapy.
  • the antagonists / agonists of the associated chemokines and the specific chemokine receptor antibodies are used to influence the cell growth to the chemokine receptors found (and analogously to other tumor cell proteome clusters).
  • an accelerated onset of tumor cell death (apoptosis) is surprisingly observed.
  • the present invention also relates to a medicament containing at least one inhibitor of at least two chemokine receptors.
  • the medicament according to the invention preferably contains antagonists of chemokine receptors, antibodies or antibody fragments, which are the binding site block the chemokine receptor at least partially.
  • a chemokine receptor-ligand interaction preferably a protein-protein (peptide) interaction with non-specific molecules, which are obtained from natural extracts, from synthetic or recombinantly produced binding proteins and from other peptide-protein libraries, is also sufficient for the to bring about a surprising effect of tumor cell apoptosis.
  • the inhibitors of at least two chemokine receptors which can be used in the medicament according to the invention can be used to produce a medicament for the treatment of tumors, inflammatory diseases, autoimmune diseases of the bone marrow and other organs, rejection reactions in transplants.
  • tumors, inflammatory diseases and autoimmune diseases of the blood system, the lymphatic system, the cardiovascular system, the nervous system, the respiratory tract, the digestive tract, the endocrine system, the skin including the appendages, the musculoskeletal system and the urogenital tract including the kidney can be treated.
  • Inhibitors or protein ligands are preferably used which are selected from the group consisting of antagonists of chemokine receptors, antibodies or antibody fragments which at least partially block the binding site of the chemokine receptor.
  • the tumors that can be treated in particular are selected from the group consisting of colorectal tumors, prostate tumors and other tumor diseases of the blood system, the lymphatic system, the cardiovascular system, the nervous system, the respiratory tract, the digestive tract, the endocrine system stem, the skin including the appendages, the musculoskeletal system and the urogenital tract including the kidney.
  • the inflammatory processes to be treated in particular are selected from the group consisting of bronchial asthma, chronic inflammatory bowel diseases, organ rejection and other inflammatory processes of the blood system, the lymphatic system, the cardiovascular system, the nervous system, the respiratory tract, the digestive tract, the endocrine system, the skin including the appendages, the musculoskeletal system and the urogenital tract including the kidney.
  • the autoimmune diseases to be treated in particular are selected from the group consisting of rheumatoid arthritis, lupus erythematosus and other chronic inflammations of the blood system, the lymphatic system, the cardiovascular system, the nervous system, the respiratory tract, the digestive tract, the endocrine system, the skin including Appendages, the musculoskeletal system and the urogenital tract including the kidney.
  • the invention further relates to the use of an inhibitor of a chemokine receptor for the manufacture of a medicament for preventing or alleviating organ rejection reactions after organ transplantation, in particular after transplantation of the heart, liver, kidney and pancreas as well as other organs, tissues and cell systems of the gastrointestinal tract, the respiratory tract and the urogenital tract , Circulatory system, the neuro-endocrinium and the musculoskeletal system as well as the blood and immune system.
  • the method according to the invention can also be used for the purpose of diagnosis and therapy.
  • the use of chemokines and their corresponding receptors, their antagonists, including antibodies was found in order to inhibit cancer growth, including metastasis, and to suppress inflammatory and autoimmune diseases.
  • the method according to the invention is based on the finding that chemokines act on specific tumor and inflammatory cells through autocrine, paracrine and endocrine routes via the disease-specific constellation of the chemokine receptor proteome. Primary and secondary tumors as well as specific inflammatory cells are controlled in their migration and proliferation behavior. Diagnostic detection of the locally increased expressed and regulated chemokines and the presence of the chemokine receptor compositions gives rise to the possibility of cancer growth, tumor metastasis and inflammatory as well To decisively suppress or completely prevent autoimmune diseases.
  • the peptides according to the invention with Seq ID No 1 to 40 can be used as epitopes for generating antibodies.
  • These sequences according to the invention are (ID 1-40):
  • X represents an amino acid residue or a peptide residue of up to 30 amino acids
  • Y represents an amino acid residue or a peptide residue of up to 30 amino acids
  • the peptides according to the invention are coupled to the protein carrier KLH (keyhole limpet hemocyanin). This coupling takes place using MBS (m-maleimidobenzoyl-N-hydroxysuccinimide ester) via a cysteine terminally integrated in the petid, or directly using carbodiimide.
  • KLH keyhole limpet hemocyanin
  • the antibodies are obtained by conventional methods by immunization, preferably from mice, rabbits, etc.
  • the methods for producing monoclonal antibodies by molecular biological methods, such as recombinant production, can also be used.
  • the antibodies are purified according to the known methods and galenically prepared for use.
  • cell preparations, cell extracts and in particular membrane isolates from overexpressing, artificially transfected chemokine receptor-carrying cells were used to generate such specific antibodies.
  • proteins based on known sequences were used as epitopes for generating antibodies. These sequences are known (ID 41-63): CCR1 ACCESSION P32246 355 aa
  • this method can also be used as follows.
  • the tumor cells whose receptor composition is to be investigated are grown in parallel in vitro, and the cells obtained therefrom are also examined for their receptor composition and treated with chemokines, preferably of the types HCC-1, HCC-2, MCP-1, RANTES or SDF-1 , In addition, the known analogues were also used.
  • chemokines preferably of the types HCC-1, HCC-2, MCP-1, RANTES or SDF-1
  • the known analogues were also used.
  • the modified Boyden migration chamber method it can be determined that the tumor cells react chemotactically when agonists that bind to the corresponding chemokine receptors are administered. The inhibition of their migration is confirmed by prior incubation with antagonists or receptor antibodies.
  • nude mice Since nude mice have a deficient immune system, the metastatic behavior in a host body can be examined in a nude mouse model without the known immune reactions between species taking place and the foreign cells being rejected. Nude mice are vaccinated in a manner known per se with tumor cells or tumor cell lines whose chemokine receptor distribution pattern had been analyzed and the metastasis by these cells is checked when treated with chemokines and when treated with chemokine antagonists and / or receptor antibodies. Surprisingly, it is found that chemokine antagonists and receptor antibodies belonging to the found receptors significantly inhibit or prevent metastasis, while the addition of chemokines leads to a modulation of tumor growth. Surprisingly, it also emerges that the preparations analyzed by immunohistochemistry show a specific distribution of chemokines and chemokine receptors in the tumor and surrounding tissue. This identified additional targeted intervention options.
  • This intervention in accordance with the method according to the invention consists in additionally expanding the proteome analysis of the chemokines and their receptors by analyzing antitumor peptides / proteins in the same method. This results in the expansion of the diagnostic and therapeutic approach, in particular to use antagonists directed against further clusters of the tumor cell surface proteome. These effects can be enhanced by a combination with chemokine receptor antagonists and antibodies.
  • tumor cell lines e.g. preferably LNCaP, PC-3, DU-145, HT-29, Caco-2, T-84
  • tumor cells settle.
  • modified cells thus preferably form metastases in the liver.
  • chemokine / chemokine receptor proteome in particular the chemokine receptors CXCR4, and CCR5 and / or CXCR3, can also be used in the rejection of Kidney transplants can be demonstrated.
  • chemokine receptors CXCR4, and CCR5 and / or CXCR3 can also be used in the rejection of Kidney transplants.
  • In vitro experiments have also shown that a mixture of antibodies and antagonists directed at these receptors strongly inhibits the migration of disease-specific effector cells.
  • Example 1 The invention is explained in more detail below with the aid of examples.
  • Example 1 The invention is explained in more detail below with the aid of examples.
  • Example 1 Example 1 :
  • chemokine receptors preferably CCR and CXCR
  • other clusters of the tumor cell surface proteome preferably CCR and CXCR
  • mice type NZW X NZB
  • the mice are used to produce monoclonal antibodies, which is carried out using the routine methods of IPF PharmaCeuticals GmbH.
  • the antibodies checked by Western blot and ELISA can be used for the above-mentioned diagnostic and therapeutic purposes if they are highly purified using the laboratory methods of IPF PharmaCeuticals GmbH.
  • the sequences used for the chemokine receptors must be selected in accordance with sequence ID 1-63.
  • chemokines and chemokine receptors Detection of chemokines and chemokine receptors in primary tumors, tumor metastases and single tumor cells.
  • the tumor cells could be obtained and analyzed by immunohistochemical methods and other molecular biological methods.
  • the primary tumor cells, the metastases and circulating single cells contain a specific composition of chemokines and chemokine receptors.
  • the algorithm of this composition is individually and tumor-dependent of high specificity, which surprisingly enables targeted tumor treatment based on the diagnosed proteome clusters using the method according to the invention.
  • the algorithms of the chemokine receptors are preferably suitable here. According to the invention, these algorithms derived from the tests are defined as follows:

Abstract

L'invention concerne la production d'un médicament et d'un moyen diagnostique par protéomique, contenant de préférence au moins deux ligands ou anticorps différents récepteurs de chimiokines, ainsi que l'utilisation d'au moins deux ligands différents récepteurs de chimiokines, deux anticorps récepteurs de chimiokines et/ou deux récepteurs de chimiokines différents. Selon l'invention, le médicament contient comme inhibiteurs de préférence des ligands ou des anticorps d'au moins deux récepteurs de chimiokines ou des algorithmes associés du protéome de surface récepteur de chimiokines. Cette invention porte aussi sur l'utilisation d'au moins un ligand récepteur de chimiokines et/ou d'un récepteur de chimiokines, sur des peptides et des anticorps, ainsi que sur leur utilisation pour le diagnostic et le traitement de maladies tumorales et d'inflammations. On peut utiliser de façon analogue des groupes de protéomes de surface de cellules tumorales analysés, tels que des ectoprotéases, des molécules d'adhérence ou différents types de récepteurs. Ladite invention concerne également un procédé destiné au diagnostic et à la thérapie, ainsi qu'à l'utilisation médicale et commerciale des chimiokines et de leurs récepteurs correspondants, leurs antagonistes, y compris d'anticorps, dans le but de freiner le développement cancéreux, y compris des métastases, et de ralentir les maladies inflammatoires et auto-immunes. Ce procédé est basé sur la constatation suivante : les chimiokines agissent sur des cellules tumorales et inflammatoires spécifiques par des moyens autocrines, paracrines et endocrines et par l'intermédiaire de la constellation du protéome récepteur de chimiokines inhérente à la maladie. Des tumeurs primaires et secondaires, ainsi que des cellules inflammatoires spécifiques sont guidées dans leur comportement de migration et de prolifération. Le diagnostic prouvant l'augmentation locale des chimiokines exprimées et régulées ainsi que la présence des compositions de récepteurs de chimiokines, il est possible de limiter notablement ou d'empêcher complètement le développement du cancer, des métastases tumorales, ainsi que celui des maladies inflammatoires et auto-immunes.
EP01923710A 2000-03-31 2001-04-02 Medicament et moyen diagnostique pour analyser le proteome de surface de cellules tumorales et inflammatoires, et pour traiter des maladies tumorales et inflammatoires, de preference au moyen d'une analyse specifique des recepteurs de chimiokines et de l'interaction de ligands recepteurs de chimioki Withdrawn EP1268554A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10016013 2000-03-31
DE10016013 2000-03-31
PCT/EP2001/003708 WO2001072830A2 (fr) 2000-03-31 2001-04-02 Medicament et moyen diagnostique pour analyser le proteome de surface de cellules tumorales et inflammatoires, et pour traiter des maladies tumorales et inflammatoires, de preference au moyen d'une analyse specifique des recepteurs de chimiokines et de l'interaction de ligands recepteurs de chimiokines

Publications (1)

Publication Number Publication Date
EP1268554A2 true EP1268554A2 (fr) 2003-01-02

Family

ID=7637100

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01923710A Withdrawn EP1268554A2 (fr) 2000-03-31 2001-04-02 Medicament et moyen diagnostique pour analyser le proteome de surface de cellules tumorales et inflammatoires, et pour traiter des maladies tumorales et inflammatoires, de preference au moyen d'une analyse specifique des recepteurs de chimiokines et de l'interaction de ligands recepteurs de chimioki

Country Status (5)

Country Link
US (1) US20030186889A1 (fr)
EP (1) EP1268554A2 (fr)
JP (1) JP2003530325A (fr)
AU (1) AU2001250412A1 (fr)
WO (1) WO2001072830A2 (fr)

Families Citing this family (93)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995019436A1 (fr) * 1994-01-13 1995-07-20 The Regents Of The University Of California Recepteurs de proteines mammaliennes monocytaires, au pouvoir chimiotactique
WO2003102589A1 (fr) * 2002-04-08 2003-12-11 Bioinfra Inc. Procede et systeme d'analyse de biomarqueurs de cancer utilisant l'extraction d'images proteomiques
KR100383529B1 (en) * 2002-04-08 2003-05-12 Biolnfra Inc Method and system for analysis of cancer biomarker using proteome image mining
US20050276812A1 (en) 2004-06-01 2005-12-15 Genentech, Inc. Antibody-drug conjugates and methods
AU2003250221A1 (en) * 2002-08-19 2004-03-11 Bayer Healthcare Ag Diagnostics and therapeutics for diseases associated with human cxc chemokine receptor 6(cxcr6)
WO2004029221A2 (fr) 2002-09-27 2004-04-08 The General Hospital Corporation Dispositif microfluidique pour la separation de cellules et utilisations de ce dispositif
CA2516138A1 (fr) * 2003-02-14 2004-09-02 Sagres Discovery, Inc. Nouveaux cibles therapeutiques du recepteur de couplage a la proteine g dans le cancer
BR122018071968B8 (pt) 2003-11-06 2021-07-27 Seattle Genetics Inc conjugado de anticorpo-droga, composição farmacêutica, artigo de manufatura e uso de um conjugado de anticorpo-droga
CA2558813A1 (fr) * 2004-03-09 2005-09-15 Kyoto University Composition medicale contenant un inhibiteur medical cxcr3
CA2501422C (fr) * 2004-04-29 2014-08-12 University Of Rochester Chimiokines lymphoides dans le diagnostic, la surveillance et le traitement de maladies auto-immunes
NZ580115A (en) 2004-09-23 2010-10-29 Genentech Inc Cysteine engineered antibody light chains and conjugates
US20100111856A1 (en) 2004-09-23 2010-05-06 Herman Gill Zirconium-radiolabeled, cysteine engineered antibody conjugates
EP1698902A1 (fr) * 2005-03-01 2006-09-06 DKFZ Deutsches Krebsforschungszentrum Utilisation de XCR1 pour le diagnostic et surveillance de la tolérance immunitaire
US20070196820A1 (en) 2005-04-05 2007-08-23 Ravi Kapur Devices and methods for enrichment and alteration of cells and other particles
US20090054322A1 (en) * 2005-05-26 2009-02-26 Rappaport Family Institute For Research In The Medical Sciences Polypeptides and compositions comprising same and methods of using same for treating cxcr4 associated medical conditions
US8921102B2 (en) 2005-07-29 2014-12-30 Gpb Scientific, Llc Devices and methods for enrichment and alteration of circulating tumor cells and other particles
JP2010521413A (ja) 2006-03-16 2010-06-24 プロタゴニスツ リミテッド 免疫系機能を改変するためのサイトカインとサイトカイン受容体の組合せ
US7879799B2 (en) * 2006-08-10 2011-02-01 Institute For Systems Biology Methods for characterizing glycoproteins and generating antibodies for same
ES2456963T3 (es) 2007-06-04 2014-04-24 Rappaport Family Institute For Research In The Medical Sciences Agentes para el tratamiento de enfermedades inflamatorias y métodos para usar los mismos
US20100227824A1 (en) * 2008-10-10 2010-09-09 Chai Ezerzer Pharmaceutical peptides for the treatment of inflammatory diseases
AU2010292172A1 (en) 2009-09-09 2012-05-03 Centrose, Llc Extracellular targeted drug conjugates
PE20130342A1 (es) 2010-04-15 2013-04-20 Spirogen Sarl Pirrolobenzodiacepinas y conjugados de las mismas
CN114246952A (zh) 2010-06-08 2022-03-29 基因泰克公司 半胱氨酸改造的抗体和偶联物
US20130109629A1 (en) 2010-06-28 2013-05-02 Universitätsklinikum Freiburg Blockade of ccl18 signaling via ccr6 as a therapeutic option in fibrotic diseases and cancer
EP2611832B1 (fr) 2010-09-02 2017-11-29 Vaccinex, Inc. Anticorps anti-cxcl13 et leurs procédés d'utilisation
EP2638068B1 (fr) * 2010-11-08 2018-12-26 Novartis AG Polypeptides se liant aux récepteurs de cxcr2
JP5889912B2 (ja) 2010-11-17 2016-03-22 ジェネンテック， インコーポレイテッド アラニニルメイタンシノール抗体コンジュゲート
JP5987053B2 (ja) 2011-05-12 2016-09-06 ジェネンテック， インコーポレイテッド フレームワークシグネチャーペプチドを用いて動物サンプルにおける治療抗体を検出するための多重反応モニタリングｌｃ−ｍｓ／ｍｓ法
MY166152A (en) * 2011-09-01 2018-06-06 Eisai R&D Man Co Ltd Anti-human xcr1 antibodies
PT2750713E (pt) 2011-10-14 2016-01-20 Genentech Inc Pirrolobenzodiazepinas e conjugados das mesmas
WO2013130093A1 (fr) 2012-03-02 2013-09-06 Genentech, Inc. Biomarqueurs pour un traitement à base de composés chimiothérapeutiques anti-tubuline
US9890213B2 (en) 2012-03-02 2018-02-13 Vaccinex, Inc. Methods for the treatment of B cell-mediated inflammatory diseases
US9328174B2 (en) 2012-05-09 2016-05-03 Novartis Ag Chemokine receptor binding polypeptides
CN104884087B (zh) * 2012-09-06 2019-07-30 阿德莱德研究创新有限公司 预防和/或治疗转移性癌症的产品和方法
WO2014057120A1 (fr) 2012-10-12 2014-04-17 Adc Therapeutics Sàrl Conjugués anticorps - pyrrolobenzodiazépine
PT2906296T (pt) 2012-10-12 2018-06-01 Medimmune Ltd Conjugados de pirrolobenzodiazepina-anticorpo
ES2680153T3 (es) 2012-10-12 2018-09-04 Adc Therapeutics Sa Conjugados de anticuerpos anti-PSMA-pirrolobenzodiazepinas
RS53818B1 (en) 2012-10-12 2015-06-30 Spirogen Sàrl PIROLOBENZODIAZEPINI I NJIHOVI conjugated
JP6270859B2 (ja) 2012-10-12 2018-01-31 エイディーシー・セラピューティクス・エス・アー・エール・エルＡｄｃ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｓａｒｌ ピロロベンゾジアゼピン−抗体結合体
CA2887895C (fr) 2012-10-12 2019-10-29 Adc Therapeutics Sarl Conjugues d'anticorps cd19-anti-pyrrolobenzodiazepine
KR101995621B1 (ko) 2012-10-12 2019-07-03 에이디씨 테라퓨틱스 에스에이 피롤로벤조디아제핀-항-cd22 항체 컨주게이트
CN105246894A (zh) 2012-12-21 2016-01-13 斯皮罗根有限公司 用于治疗增殖性和自身免疫疾病的非对称吡咯并苯并二氮杂卓二聚物
CN110452242A (zh) 2012-12-21 2019-11-15 麦迪穆有限责任公司 吡咯并苯并二氮杂卓及其结合物
KR102176962B1 (ko) 2013-01-31 2020-11-10 백시넥스 인코포레이티드 면역글로불린 a 수준을 증가시키기 위한 방법
JP6340019B2 (ja) 2013-03-13 2018-06-06 メドイミューン・リミテッドＭｅｄＩｍｍｕｎｅ Ｌｉｍｉｔｅｄ ピロロベンゾジアゼピン及びそのコンジュゲート
KR102057755B1 (ko) 2013-03-13 2019-12-19 메디뮨 리미티드 피롤로벤조디아제핀 및 그의 컨쥬게이트
CA2905181C (fr) 2013-03-13 2020-06-02 Medimmune Limited Pyrrolobenzodiazepines et ses conjugues servant a fournir une therapie ciblee
KR20160042080A (ko) 2013-08-12 2016-04-18 제넨테크, 인크. 1-(클로로메틸)-2,3-디히드로-1H-벤조[e]인돌 이량체 항체-약물 접합체 화합물, 및 사용 및 치료 방법
US9956299B2 (en) 2013-10-11 2018-05-01 Medimmune Limited Pyrrolobenzodiazepine—antibody conjugates
US9950078B2 (en) 2013-10-11 2018-04-24 Medimmune Limited Pyrrolobenzodiazepine-antibody conjugates
GB201317982D0 (en) 2013-10-11 2013-11-27 Spirogen Sarl Pyrrolobenzodiazepines and conjugates thereof
EP3054983B1 (fr) 2013-10-11 2019-03-20 Medimmune Limited Conjugués anticorps-pyrrolobenzodiazépines
MX2016007826A (es) 2013-12-16 2017-03-31 Genentech Inc Compuestos peptidomimeticos y sus conjugados de anticuerpo-farmaco.
WO2015095212A1 (fr) 2013-12-16 2015-06-25 Genentech, Inc. Composés conjugués anticorps-médicament dimérique à base de 1-(chlorométhyl)-2,3-dihydro-1 h-benzo [e]indole, et méthodes d'utilisation et de traitement
JP6671292B2 (ja) 2013-12-16 2020-03-25 ジェネンテック， インコーポレイテッド ペプチド模倣化合物及びその抗体−薬物コンジュゲート
WO2016037644A1 (fr) 2014-09-10 2016-03-17 Medimmune Limited Pyrrolobenzodiazépines et leurs conjugués
GB201416112D0 (en) 2014-09-12 2014-10-29 Medimmune Ltd Pyrrolobenzodiazepines and conjugates thereof
KR20170052600A (ko) 2014-09-12 2017-05-12 제넨테크, 인크. 시스테인 가공된 항체 및 콘주게이트
EP3191134B1 (fr) 2014-09-12 2019-11-20 Genentech, Inc. Intermédiaires disulfure d'anthracycline, conjugué anticorps-médicaments et procédés
CA2959689A1 (fr) 2014-09-17 2016-03-24 Genentech, Inc. Pyrrolobenzodiazepines et conjugues a base de disulfure d'anticorps associes
EP3223854A1 (fr) 2014-11-25 2017-10-04 ADC Therapeutics SA Conjugués anticorps-pyrrolobenzodiazépine
CN107206101B (zh) 2014-12-03 2021-06-25 基因泰克公司 季铵化合物及其抗体-药物缀合物
GB201506402D0 (en) 2015-04-15 2015-05-27 Berkel Patricius H C Van And Howard Philip W Site-specific antibody-drug conjugates
GB201506411D0 (en) 2015-04-15 2015-05-27 Bergenbio As Humanized anti-axl antibodies
MA43345A (fr) 2015-10-02 2018-08-08 Hoffmann La Roche Conjugués anticorps-médicaments de pyrrolobenzodiazépine et méthodes d'utilisation
MA43354A (fr) 2015-10-16 2018-08-22 Genentech Inc Conjugués médicamenteux à pont disulfure encombré
MA45326A (fr) 2015-10-20 2018-08-29 Genentech Inc Conjugués calichéamicine-anticorps-médicament et procédés d'utilisation
GB201601431D0 (en) 2016-01-26 2016-03-09 Medimmune Ltd Pyrrolobenzodiazepines
GB201602359D0 (en) 2016-02-10 2016-03-23 Medimmune Ltd Pyrrolobenzodiazepine Conjugates
GB201602356D0 (en) 2016-02-10 2016-03-23 Medimmune Ltd Pyrrolobenzodiazepine Conjugates
JP6943872B2 (ja) 2016-03-25 2021-10-06 ジェネンテック， インコーポレイテッド 多重全抗体及び抗体複合体化薬物定量化アッセイ
GB201607478D0 (en) 2016-04-29 2016-06-15 Medimmune Ltd Pyrrolobenzodiazepine Conjugates
PL3458101T3 (pl) 2016-05-20 2021-05-31 F. Hoffmann-La Roche Ag Koniugaty PROTAC-przeciwciało i sposoby ich stosowania
US20170370906A1 (en) 2016-05-27 2017-12-28 Genentech, Inc. Bioanalytical analysis of site-specific antibody drug conjugates
US10639378B2 (en) 2016-06-06 2020-05-05 Genentech, Inc. Silvestrol antibody-drug conjugates and methods of use
CN109689111B (zh) 2016-08-11 2024-04-05 基因泰克公司 吡咯并苯并二氮杂䓬前药及其抗体缀合物
CN110139674B (zh) 2016-10-05 2023-05-16 豪夫迈·罗氏有限公司 制备抗体药物缀合物的方法
GB201617466D0 (en) 2016-10-14 2016-11-30 Medimmune Ltd Pyrrolobenzodiazepine conjugates
GB201702031D0 (en) 2017-02-08 2017-03-22 Medlmmune Ltd Pyrrolobenzodiazepine-antibody conjugates
US11160872B2 (en) 2017-02-08 2021-11-02 Adc Therapeutics Sa Pyrrolobenzodiazepine-antibody conjugates
CN110582505B (zh) 2017-04-18 2021-04-02 免疫医疗有限公司 吡咯并苯并二氮杂*缀合物
CN110536703A (zh) 2017-04-20 2019-12-03 Adc治疗有限公司 使用抗axl抗体-药物缀合物的组合疗法
US11318211B2 (en) 2017-06-14 2022-05-03 Adc Therapeutics Sa Dosage regimes for the administration of an anti-CD19 ADC
SI3668874T1 (sl) 2017-08-18 2022-04-29 Medimmune Limited Pirolobenzodiazepinski konjugati
RU2020113749A (ru) 2017-09-20 2021-10-20 пиЭйч ФАРМА Ко., ЛТД. Аналоги таиланстатина
GB201803342D0 (en) 2018-03-01 2018-04-18 Medimmune Ltd Methods
GB201806022D0 (en) 2018-04-12 2018-05-30 Medimmune Ltd Pyrrolobenzodiazepines and conjugates thereof
GB201814281D0 (en) 2018-09-03 2018-10-17 Femtogenix Ltd Cytotoxic agents
AU2019365238A1 (en) 2018-10-24 2021-05-13 F. Hoffmann-La Roche Ag Conjugated chemical inducers of degradation and methods of use
EP3894427A1 (fr) 2018-12-10 2021-10-20 Genentech, Inc. Peptides de photoréticulation pour conjugaison spécifique de site à des protéines contenant fc
GB201901197D0 (en) 2019-01-29 2019-03-20 Femtogenix Ltd G-A Crosslinking cytotoxic agents
TW202216771A (zh) 2020-06-26 2022-05-01 德商拜耳廠股份有限公司 用於治療應用之ccr8抗體
GB2597532A (en) 2020-07-28 2022-02-02 Femtogenix Ltd Cytotoxic compounds

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL78444A (en) * 1986-04-08 1992-05-25 Yeda Res & Dev Human gamma interferon-specific receptor protein,antibody against said protein,and compositions containing said protein and antibody
US6448379B1 (en) * 1993-09-14 2002-09-10 Chiron Corporation IL8 inhibitors
AU3681795A (en) * 1994-09-23 1996-04-09 University Of Nebraska Board Of Regents Polypeptide agonists and antagonists of human interleukin-8
WO1998006398A1 (fr) * 1996-08-15 1998-02-19 Smithkline Beecham Corporation Antagonistes du recepteur il-8
AU4820399A (en) * 1998-06-29 2000-01-17 Hyseq, Inc. A chemokine receptor obtained from a cdna library of fetal liver-spleen

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0172830A2 *

Also Published As

Publication number Publication date
WO2001072830A2 (fr) 2001-10-04
WO2001072830A3 (fr) 2002-06-20
US20030186889A1 (en) 2003-10-02
AU2001250412A1 (en) 2001-10-08
JP2003530325A (ja) 2003-10-14

Similar Documents

Publication Publication Date Title
EP1268554A2 (fr) Medicament et moyen diagnostique pour analyser le proteome de surface de cellules tumorales et inflammatoires, et pour traiter des maladies tumorales et inflammatoires, de preference au moyen d'une analyse specifique des recepteurs de chimiokines et de l'interaction de ligands recepteurs de chimioki
DE69628652T2 (de) Vegf-verwandtes protein
DE69736712T2 (de) Verfahren zur milderung von neuropatischen schmerz mit prosaposin verwandten peptiden
DE69635565T2 (de) Antagonisten des vaskulären Endothelzellen-Wachstumfaktors
DE69936315T2 (de) Fragmente des wachstumsfaktors für bindegewebe (ctgf) und verfahren und anwendungen davon
JP3115561B2 (ja) 白血球を増加させるための医薬組成物の製造方法
DE69729125T2 (de) Troponin untereinheiten und fragmente zur verwendung als inhibitoren der angiogenese
DE69934425T2 (de) Thrombopoietin substitute
DE69727558T2 (de) Humanes CYR61, ein Signalmolekül der extrazellularen Matrix
DE69532767T2 (de) Peptid umfassend eine Sequenz aus einer Fusionsverbindungsstelle in einem mutierten EGF-Rezeptor vom Typ III
DE69433552T2 (de) An den zelloberflächenrezeptor hek bindendes cytokin
DE69635675T2 (de) Verkürzter aus einer gliazelllinie gewonnener neurotropher faktor
EP0167575B2 (fr) Cardiodilatine, une hormone peptidique et son procede de fabrication
DE60217326T2 (de) Von neurofilamentproteinen abgeleitete peptide und deren medizinische verwendung
DE69532436T2 (de) Einzelkettenformen des clycoprotein-hormon-quartetts
DE69734141T2 (de) PROTEIN, DAS FÜR MENSCHLICHE Th2-ZELLEN SPEZIFISCH IST, DAFÜR KODIERENDES GEN UND KORRESPONDIERENDE TRANSFORMANTE, REKOMBINANTER VEKTOR UND MONOKLONALER ANTKÖRPER
DE69931482T2 (de) Isolierte peptide die aminosäuresequenzen von ny-eso-1 entsprechen und an mhc-klasse i und mhc klasse ii moleküle binden, und deren verwendungen
DE60207043T2 (de) Histidin-reiches glykoprotein (hrgp) zur inhibierung der angiogenese
EP1644028B1 (fr) Substances a activite biologique du peptide intestinal vasoactif pour le traitement d'affections pulmonaires interstitielles
DE69920405T2 (de) Verwendung des heregulins als epithelzellenwachstumsfaktor
DE60103078T2 (de) Chemokin mutanten zur behandlung multipler sklerose
WO1997023611A2 (fr) Sequences d'acide nucleique de genes des proteines du groupe a grande mobilite et leurs utilisations
EP2363412B1 (fr) Antagonistes Utilises Contre L'Interaction de PF4 et de RANTES
DE4200043A1 (de) Lymphoides cd30-antigen (ki-1), dessen protein- und die zugehoerige nucleotidsequenz, seine herstellung sowie mittel zur diagnose und untersuchung von tumoren
DE4038189C2 (de) Humanes, Epididymis-spezifisches Polypeptid und dessen Verwendung zur Therapie und Diagnose männlicher Infertilität

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20020926

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: IPF PHARMACEUTICALS GMBH

RIN1 Information on inventor provided before grant (corrected)

Inventor name: FORSSMANN, ULF

Inventor name: FORSSMANN, WOLF-GEORG

Inventor name: ADERMANN, KNUT

Inventor name: HEITLAND, ALEKSANDRA

Inventor name: SPODSBERG, NIKOLAJ

17Q First examination report despatched

Effective date: 20040806

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20070319