WO2004024178A1 - Antagonistes de recepteur cxcr4 - Google Patents

Antagonistes de recepteur cxcr4 Download PDF

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Publication number
WO2004024178A1
WO2004024178A1 PCT/EP2003/009691 EP0309691W WO2004024178A1 WO 2004024178 A1 WO2004024178 A1 WO 2004024178A1 EP 0309691 W EP0309691 W EP 0309691W WO 2004024178 A1 WO2004024178 A1 WO 2004024178A1
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Prior art keywords
cells
cll
chemokine receptor
receptor antagonist
cell
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PCT/EP2003/009691
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German (de)
English (en)
Inventor
Jan Andreas Burger
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Jan Andreas Burger
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Priority to AU2003255501A priority Critical patent/AU2003255501A1/en
Publication of WO2004024178A1 publication Critical patent/WO2004024178A1/fr

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    • 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
    • A61K38/10—Peptides having 12 to 20 amino acids
    • 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
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to the use of a chemokine receptor antagonist as a ligand for the CXCR4 receptor for apoptosis-inducing treatment and / or for preventing metastasis of cancer cells in a patient.
  • CLL chronic lymphocytic leukemia
  • the pathogenesis of CLL is characterized in that the circulating leukemia cells are in the G 0 / Gr phase of the cell cycle and accumulate in the patient due to a defect in programmed cell death (apoptosis). For this reason, the increased number of leukemia cells in this disease is not due to an accelerated cell division, but to an apoptosis defect. This apoptosis resistance is believed to be responsible for the poor response of CLL patients to standard chemotherapy. Despite the longevity of the CLL cells in vivo, spontaneous apoptosis of CLL cells occurs in vitro under culture conditions which normally allow the growth of B cell lines.
  • the bone marrow is a complex tissue in which hematopoietic stem cells and the cell rows derived from them are in close contact with a network of connective tissue cells of mesenchymal origin, collectively referred to as "stroma".
  • SDF-1 stromal cell-derived factor-1
  • the chemokine "stromal cell-derived factor-1" (SDF-1) plays an important role in B-cell development.
  • stromal cells secrete large amounts of SDF-1, which binds to the CXCR4 receptor of B cells.
  • SDF-1 regulates the development of B cells by retention of immature B lymphocytes in the supportive bone marrow microenvironment, so that premature flushing out of these cells into the peripheral blood is prevented.
  • SDF-1 can also act as a direct B cell growth factor and as an anti-apoptotic factor for CLL cells (Burger et al. Blood 96: 2655-2663, 2000, Burger et al., Leukemia & Lymphoma 43: 461-466, 2002).
  • B lymphocytes are cultured together with adherent stromal cells.
  • the B cells in these cultures adhere to stroma cells and migrate spontaneously between or under the adherent stroma cell layer, comparable to the adherence and spontaneous migration of CLL cells under bone marrow stromal cells (pseudo-temperie polesis).
  • Bone cells which differentiate in long-term culture from peripheral mononuclear cells of CLL patients, are in close contact with CLL cells and protect the CLL cells from apoptosis by secretion of SDF-1 (Burger et al. Blood 96: 2655-2663, 2000).
  • chemokine receptor antagonists have been developed as antiviral drugs with the goal of To prevent progression of HIV infection towards AIDS.
  • These chemokine receptor antagonists include monoclonal antibodies against the CXCR4 receptor, the bizyklam derivative AMD3100 and polyphemusin peptide analogs (DE 198 01 265; Arakaki et al., J. Virol. 73: 1719-23, 1999; Tamamura et al., Bioorg. Med. Chem. Lett. 11: 1897-1902, 2001).
  • Alkylating agents chlorambucil and cyclophosphamide
  • chlorambucil and cyclophosphamide have been the first choice for treating B-CLL for around 30 years and can cause partial remissions in the majority of patients.
  • purine analogues flurarabine and 2-CdA, monoclonal antibodies.
  • anti-CD52, anti-CD20 mAbs high-dose chemotherapy with transplantation of haematopoietic stem cells, radioimmunotherapy or gene therapy, the CLL is still not curable. No decisive improvement in survival and thus the natural course of the disease has been demonstrated for any of the therapies mentioned.
  • SCLC small cell bronchial carcinoma
  • CXCR4 chemokine receptors which play a role in the metastasis of these tumor cells.
  • chemokine receptor antagonist as a ligand for the CXCR4 receptor Apoptosis inducing treatment and / or for preventing metastasis of cancer cells expressing the CXCR4 receptor in a patient.
  • patient means any mammal, including humans.
  • stromal cells encompasses connective tissue cells of mesenchymal origin which are in close contact with the hematopoietic stem cells and the cell rows derived therefrom in the bone marrow, but also outside the bone marrow e.g. can be found in the secondary lymphatic tissues.
  • the term “nurse cells” encompasses accessory cells necessary for the survival of cancer cells (e.g. CLL cells) and / or the metastasis of cancer cells (e.g. SCLC cells) which express the CXCR4 receptor.
  • the so-called “nurse cells” secrete growth factors or chemokines (e.g. SDF-1) and express adhesion molecules that promote the survival and chemotaxis of cancer cells.
  • a growth factor that is secreted by stromal cells and / or nurse cells is, for example, the chemokine "stromal cell derived factor 1" (SDF1), which binds to the CXCR4 receptor on CLL cells.
  • urse cells is not limited to SDF-1 secreting cells and / or differentiated mononuclear cells from CLL patients, but encompasses any accessory cells that are responsible for the survival of cancer cells and / or the metastasis of cells that have the CXCR4 receptor express, favor.
  • chemokine receptor antagonist encompasses any natural or synthetic ligand that binds to and / or interacts with the CXCR4 receptor to inhibit and / or block its function.
  • the chemokine receptor antagonist can be a peptide-like molecule, such as a polyphemusin II peptide or a biologically active derivative thereof, and / or a non-peptide-like molecule, such as a bizyclame derivative or a biologically active derivative thereof.
  • biologically active derivative in this context means that this derivative is also present on the CXCR4- Receptor binds and / or can interact with it to inhibit and / or block its function.
  • Preferred chemokine receptor antagonists of the present invention are polyphemusin II peptides.
  • Particularly preferred chemokine receptor antagonists of the present invention are the polyphemusin II peptides T 140 (Seq ID No. 1), TC 14012 (Seq ID No. 2) and TN 14003 (Seq ID No. 3), biologically active derivatives thereof and at least two mixtures thereof containing these peptides.
  • the polyphemusin II peptides T 140 (Seq ID No. 1), TC 14012 (Seq ID No. 2) and TN 14003 (Seq ID No. 3) consist of 14 amino acids and have the known chemokine receptor Antagonists have the highest potency in blocking the CXCR4 receptor for the chemokine SDF1.
  • TC1412 and TN 14003 also show greater stability in the patient's serum.
  • preferred chemokine receptor antagonists are also bizyklam derivatives.
  • the bizyklam AMD3100 which consists of two cyclam units (1, 4,8,11-tetraazazyclotetradecane), which are linked to one another by an aromatic methylene linker, is particularly preferred as the chemokine receptor antagonist.
  • CXCR4 receptor-expressing cancer cells are cells of the lymphatic system, such as chronic lymphocytic leukemia (CLL) cells.
  • CLL chronic lymphocytic leukemia
  • the cancer cells are small cell bronchial carcinoma (SCLC) cells or tumor cells from patients with breast cancer, prostate cancer, malignant melanoma, neuroblastoma or renal cell carcinoma.
  • SCLC small cell bronchial carcinoma
  • stromal and / or nurse cell-affine cancer cells includes cancer cells which are expressed by growth factors, chemokines and / or other messenger substances and / or by stromal and / or nurse cells are secreted, "attracted”, ie they migrate to the place where the stroma and / or nurse cells are located.
  • the chemokine receptor antagonists used according to the invention can be administered to a patient alone or in combination with other drugs in a pharmaceutically effective amount.
  • a suitable concentration of a polyphemusin II peptide is, for example, a dose of 10 to 1000 ⁇ g / kg body weight, preferably 50 to 500 ⁇ g / kg body weight, even more preferably 100 to 300 ⁇ g / kg body weight.
  • a suitable concentration of a bizyklam derivative is, for example, a dose of 10 to 160 ⁇ g / kg body weight, preferably 30 to 120 ⁇ g / kg body weight, more preferably 50 to 100 ⁇ g / kg body weight.
  • the chemokine receptor antagonists used according to the invention are not restricted in terms of the formulation and can be administered orally, rectally, by infusion, injection, inhalation and topically in suitable pharmaceutical carriers, auxiliaries and / or diluents.
  • a chemokine receptor antagonist as a ligand for the CXCR4 receptor for apoptosis-inducing treatment and / or for the prevention of metastasis of cancer cells which express the CXCR4 receptor, surprisingly, is a highly specific method of treatment in a patient of cancer diseases for which an efficient therapeutic procedure is not yet available.
  • the above method enables selective induction of apoptosis in CLL cells.
  • this method also offers an effective possibility of inhibiting and / or preventing the metatasis of, for example, SCLC cells.
  • FIG. 1 shows a bar diagram which describes the inhibition of chemotaxis of CLL cells after stimulation by SDF-1 ⁇ by the chemokine receptor antagonist T140;
  • FIG. 2 shows a line diagram which describes the inhibition of F-actin polymerization of CLL cells after stimulation by SDF-1 ⁇ by the chemokine receptor antagonist T 140;
  • FIG. 3 shows a bar diagram which shows the inhibition of the migration of CLL cells under bone marrow stromal cells (pseudo-temperie polesis PEP) by the chemokine receptor antagonist T140;
  • FIG. 4 shows a Western blot which describes the inhibition of p44 / 42 MAPK activation in CLL cells after stimulation with SDF-1 ⁇ by the chemokine receptor antagonist T140;
  • FIG. 5 shows a bar diagram which describes the inhibition of the anti-apoptotic effect of SDF-1 in CLL cells by the chemokine receptor antagonist T140.
  • Example 1 Inhibition of chemotaxis of CLL cells after stimulation with SDF-1 ⁇ by the chemokine receptor antagonist T140
  • the chemokine-induced migration (SDF-1 - induced) of CLL cells is passed through 5 ⁇ m micropore filters with subsequent Quantification of the migrated cells measured (Burger et al., Blood 94: 3658-3667, 1999).
  • the lymphocytes of patients with CLL are entered with or without the chemokine receptor antagonist T 140 in 2-chamber chemotaxis assays and stimulated to chemotaxis by synthetic SDF-1 ⁇ .
  • the chemokine receptor antagonist T140 inhibits the chemotaxis of CLL cells by 81 ( ⁇ 7%) at 100 ⁇ g T140.
  • the further data are shown in FIG. 1. The values are mean values ( ⁇ standard deviation) from tests with 10 different patient samples.
  • Example 2 Inhibition of actin polymerization of CLL cells after stimulation with SDF-1 ⁇ by the chemokine receptor antagonist T 140
  • the filamentous actin content (F-actin) is determined after treatment with synthetic SDF-1 ⁇ in FITC-phalloidin-labeled, permeabilized and fixed CLL cells by means of flow cytometry. Reorganization of the actin cytoskeleton is an early event in cell migration in response to chemotherapy (Burger et al., Blood 94: 3658-3667, 1999).
  • the CLL cells are preincubated with or without chemokine receptor antagonists and stimulated to actin polymerization by synthetic SDF-1 ⁇ .
  • the chemokine receptor antagonist T140 practically completely inhibits actin polymerization in CLL cells depending on the dose.
  • CLL cells are co-cultivated with bone marrow stromal cells (Burger et al., Blood 94: 3658-3667, 1999).
  • the CLL cells migrate spontaneously under the stromal cells. This migration can be inhibited to more than 80% by pretreatment with the chemokine receptor antagonist T140 (see FIG. 3).
  • T140 chemokine receptor antagonist
  • Example 4 Inhibition of p44 / 42 MAPK activation in CLL cells after stimulation with SDF-1 ⁇ by the chemokine receptor antagonist T140
  • the p42 / 44 MAPK protein content is determined in CLL cells after stimulation with SDF-1 (Burger et al., Blood 96: 2655-2663, 2000). This signal transduction pathway plays a crucial role in the survival and apoptosis (spontaneous cell death) resistance of CLL cells.
  • CLL cells are treated with synthetic SDFI ⁇ .
  • Western blots can activate p44 / 42 MAP- using p42 / 44 and phospho-p42 / 44-specific MAPK antibodies (rabbit, polyclonal, phosphorylation-specific against Thr202 / Tyr204, New England BioLabs, Beverly, MA).
  • Kinases are detected.
  • T140 the chemokine receptor antagonist
  • Example 5 Inhibition of the anti-apoptotic effect of SDF-1 ⁇ in CLL cells by the chemokine receptor antagonist T140
  • CLL cells are incubated in vitro with and without chemokine receptor antagonist T 140 and with synthetic SDF-1 ⁇ , which inhibits the death of CLL cells in culture.
  • the survivability of the cells is measured (Burger et al., Blood 96: 2655 - 2663, 2000), whereby the in vitro effect of the SDF-1 ⁇ on the survival of the CLL cells is completely abolished by the chemokine receptor antagonist (see Figure 5).
  • Seq ID no. 1

Abstract

La présente invention concerne l'utilisation d'un antagoniste de récepteur de chimiokine sous forme de ligand pour le récepteur CXCR4, afin de traiter par induction d'apoptose et/ou de prévenir la formation de métastases de cellules cancéreuses chez un patient.
PCT/EP2003/009691 2002-08-30 2003-09-01 Antagonistes de recepteur cxcr4 WO2004024178A1 (fr)

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Application Number Priority Date Filing Date Title
AU2003255501A AU2003255501A1 (en) 2002-08-30 2003-09-01 Cxcr4 receptor antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10240064.4 2002-08-30
DE10240064A DE10240064A1 (de) 2002-08-30 2002-08-30 CXCR4-Rezeptor-Antagonisten

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007049771A1 (fr) 2005-10-28 2007-05-03 Ono Pharmaceutical Co., Ltd. Compose contenant un groupe basique et son utilisation
WO2007058322A1 (fr) 2005-11-18 2007-05-24 Ono Pharmaceutical Co., Ltd. Composé contenant un groupe basique et son utilisation
US8008312B2 (en) 2005-01-07 2011-08-30 Emory University CXCR4 antagonists for the treatment of HIV infection
US8080659B2 (en) 2006-07-11 2011-12-20 Emory University CXCR4 antagonists including diazine and triazine structures for the treatment of medical disorders
WO2011098762A3 (fr) * 2010-02-10 2012-01-19 Affitech Research As Anticorps
WO2012095849A1 (fr) 2011-01-10 2012-07-19 Biokine Therapeutics Ltd. Peptides et compositions pour le traitement de tumeurs issues du neuroectoderme et de rétinoblastomes
US8338448B2 (en) 2008-03-28 2012-12-25 Altiris Therapeutics, Inc. Chemokine receptor modulators
US8410059B2 (en) 2002-08-27 2013-04-02 Biokine Therapeutics Ltd. CXCR4 antagonist and use thereof
US8440199B2 (en) 2007-12-12 2013-05-14 Imperial Innovations Limited Methods for mobilizing mesenchymal stem cells in a patient
US8455450B2 (en) 2006-12-21 2013-06-04 Biokine Therapeutics Ltd. Methods for obtaining a therapeutically effective amount of hematopoietic precursor cells and long term engraftment thereof
WO2013160895A1 (fr) 2012-04-24 2013-10-31 Biokine Therapeutics Ltd. Peptides et leur utilisation dans le traitement du cancer du poumon à grandes cellules
WO2014155376A1 (fr) 2013-03-24 2014-10-02 Biokine Therapeutics Ltd. Méthodes de traitement de la leucémie myéloïde
WO2015063768A1 (fr) 2013-10-31 2015-05-07 Biokine Therapeutics Ltd. Méthodes de traitement de la leucémie myéloïde aiguë avec mutation de la flt3
WO2015114638A2 (fr) 2014-02-03 2015-08-06 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Méthode d'élimination de cellules souches
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US8008312B2 (en) 2005-01-07 2011-08-30 Emory University CXCR4 antagonists for the treatment of HIV infection
US8114884B2 (en) 2005-01-07 2012-02-14 Emory University CXCR4 antagonists for the treatment of medical disorders
WO2007049771A1 (fr) 2005-10-28 2007-05-03 Ono Pharmaceutical Co., Ltd. Compose contenant un groupe basique et son utilisation
EP2657235A1 (fr) 2005-10-28 2013-10-30 Ono Pharmaceutical Co., Ltd. Composé contenant un groupe basique et son utilisation
WO2007058322A1 (fr) 2005-11-18 2007-05-24 Ono Pharmaceutical Co., Ltd. Composé contenant un groupe basique et son utilisation
US8080659B2 (en) 2006-07-11 2011-12-20 Emory University CXCR4 antagonists including diazine and triazine structures for the treatment of medical disorders
EP2759302A2 (fr) 2006-12-21 2014-07-30 Biokine Therapeutics LTD. 4F-benzoyl-TN14003 combiné avec rituximab pour une utilisation dans le traitement d'une tumeure
US8765683B2 (en) 2006-12-21 2014-07-01 Biokine Therapeutics Ltd. T-140 peptide analogs having CXCR4 super-agonist activity for cancer therapy
US8455450B2 (en) 2006-12-21 2013-06-04 Biokine Therapeutics Ltd. Methods for obtaining a therapeutically effective amount of hematopoietic precursor cells and long term engraftment thereof
EP3011961A1 (fr) 2006-12-21 2016-04-27 Biokine Therapeutics LTD. 4F-benzoyl-TN14003 pour la mobilisation des cellules hématopoiétiques progénitrices en vue d'une transplantation
US8663651B2 (en) 2006-12-21 2014-03-04 Biokine Therapeutics Ltd. T-140 peptide analogs having CXCR4 super-agonist activity for immunomodulation
US8440199B2 (en) 2007-12-12 2013-05-14 Imperial Innovations Limited Methods for mobilizing mesenchymal stem cells in a patient
US8338448B2 (en) 2008-03-28 2012-12-25 Altiris Therapeutics, Inc. Chemokine receptor modulators
US9314468B2 (en) 2008-03-28 2016-04-19 Altiris Therapeutics, Inc. Chemokine receptor modulators
EP2664618A2 (fr) 2008-03-28 2013-11-20 Altiris Therapeutics Modulateurs du récepteur de chimiokine
US9427456B2 (en) 2009-06-14 2016-08-30 Biokine Therapeutics Ltd. Peptide therapy for increasing platelet levels
WO2011098762A3 (fr) * 2010-02-10 2012-01-19 Affitech Research As Anticorps
US8748107B2 (en) 2010-02-10 2014-06-10 Affitech Research As Isolated antibodies which bind to CXC chemokine receptor 4
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US9353185B2 (en) 2010-02-10 2016-05-31 Affitech Research As Antibodies
WO2012095849A1 (fr) 2011-01-10 2012-07-19 Biokine Therapeutics Ltd. Peptides et compositions pour le traitement de tumeurs issues du neuroectoderme et de rétinoblastomes
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WO2014155376A1 (fr) 2013-03-24 2014-10-02 Biokine Therapeutics Ltd. Méthodes de traitement de la leucémie myéloïde
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US11642393B2 (en) 2015-07-16 2023-05-09 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
US11638742B2 (en) 2015-07-16 2023-05-02 Biokine Therapeutics Ltd. Compositions and methods for treating cancer
US10993985B2 (en) 2016-02-23 2021-05-04 BioLmeRx Ltd. Methods of treating acute myeloid leukemia
WO2020065647A1 (fr) 2018-09-25 2020-04-02 Biolinerx Ltd. Procédés de sélection d'un traitement contre un cancer associé aux récepteurs cxcr4

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