WO2011144744A1 - Composé radioactif ciblé pour cd66 humain pour le traitement de troubles - Google Patents

Composé radioactif ciblé pour cd66 humain pour le traitement de troubles Download PDF

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Publication number
WO2011144744A1
WO2011144744A1 PCT/EP2011/058274 EP2011058274W WO2011144744A1 WO 2011144744 A1 WO2011144744 A1 WO 2011144744A1 EP 2011058274 W EP2011058274 W EP 2011058274W WO 2011144744 A1 WO2011144744 A1 WO 2011144744A1
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Prior art keywords
trc
administration
radionuclide
therapeutic
antibody
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PCT/EP2011/058274
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English (en)
Inventor
Ivan Benes
Kim Orchard
Klaus Bosslet
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Therapharm Gmbh
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Publication of WO2011144744A1 publication Critical patent/WO2011144744A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1027—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against receptors, cell-surface antigens or cell-surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/48—Reproductive organs
    • A61K35/51—Umbilical cord; Umbilical cord blood; Umbilical stem cells
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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]

Definitions

  • the present invention relates to the use of targeted radioactive compounds (TRC) for the treatment of inflammatory and/or autoimmune disorders, as well as immunosuppressive disorders.
  • TRC targeted radioactive compounds
  • inflammatory/autoimmune diseases such as severe rheumatoid arthritis, multiple sclerosis, scleroderma pigmentosa, systemic lupus erythematodes, colitis ulcerosa, Crohn's disease as well as the majority of malignant diseases cannot be cured with the actual therapeutic approaches.
  • the previously mentioned inflammatory/autoimmune diseases are caused by an uncontrolled activation of the immune system against self-antigens of the patient.
  • the actual therapies directed against mediators of the disease such as cytokines and/or their receptors can delay the progression of the disease but can not hinder the progression finally resulting in complete disablement.
  • an antibody targeted radio therapy (ATRT) procedure with anti CD66 allows to treat and cure patients with non- malignant disorders such as inflammatory disorders, autoimmune disorders, immunosuppressive disorders, if combined with haematopoietic stem cell transplantation.
  • ATRT antibody targeted radio therapy
  • ATRT with anti CD66 allows localizing high doses of yttrium-90 to bone marrow and spleen.
  • ATRT with anti CD66 antibody was given to patients without any detectable side effect.
  • treatment related death was 0 percent in contrast to conventional transplantation regimens where 10-15% of patients die as a consequence to transplantation procedure related side effects.
  • the inventors have also shown in a limited number of patients with myeloma or leukemias that the treatment procedure induced a high complete remission rate resulting in long term survivors both in the autologous as well as allogeneic haematopoietic stem cell transplantation regimen.
  • the innovative changes in this treatment regimen are the elimination of antitumor agents such as high dose melphalan treatment the bone marrow reconstitution with autologous or allogeneic haematopoietic stem cells and the ATRT with reduced doses compared to the regimen applied to patients with leukemias or myeloma.
  • the allogeneic haematopoietic stem cells can be obtained from cord blood and extended in vitro using for example peptide ligands which bind to receptors on stem cells allowing the extension of stem cells under in vitro conditions.
  • Preferred media for expanding stem cells under in vitro conditions may comprise cytokines and/or interleukins, e.g.
  • TPO thrombopoietin
  • G-CSF granulocyte- stimulating factor
  • SCF stem cell factor
  • IL-3 interleukin-3
  • IL-6 interleukin-6
  • Intravenous injection of the autologous or allogeneic stem cells in patients whose bone marrow was depleted with ATRT will result in repopulation of the bone marrow niches and will transfer a normal immune system into the recipients.
  • Haematopoietic stem cell recipients who previously had autoimmune disease will be cured since the diseased autoimmune system of the patients is now reconstituted with healthy unprimed bone marrow of allogeneic donors.
  • stem cells preferably have to be free of any primed T-cells which may be the cause of allogeneic host versus graft reactions
  • recipients should have a life without autoimmune disease and without the need for medication with immunosuppressive drugs.
  • autologous stem cells e.g. bone marrow-derived stem cells, may be transplanted.
  • a subject matter of the present application is the use of a targeted radioactive compound (TRC) for the manufacture of a medicament for the administration in the therapy of a disorder selected from inflammatory and/or autoimmune disorders as well as immunosuppressive disorders, particularly in a human patient, wherein the TRC comprises a CD66-binding component which may be covalently bound to a radionuclide.
  • TRC targeted radioactive compound
  • the term "inflammatory and/or autoimmune disorders” particularly relates to disorders which are accompanied by, associated with or caused by inflammation and/or autoimmune reactions, e.g. rheumatoid arthritis and other types of arthritic disorders, multiple sclerosis and other neurodegenerative disorders, scleroderma pigmentosa, systemic lupus erythematodes, and disorders of the gastrointestinal system such as colitis ulcerosa and Crohn' disease.
  • the term “immunosuppressive disorders” relates to disorders which are accompanied by, associated with or caused by a suppression of the immune system, e.g.
  • immunodeficiency viruses such as HIV
  • CVIDs common variable immunodeficiency disorders
  • haematopoietic stem cells In the case of patients with HIV, it is preferred to transfer haematopoietic stem cells from allogeneic donors who have a mutated receptor e.g. selected from chemokine receptor CCR2, CCR5 or SDF1 not allowing HIV to infect T- cells. After bone marrow depletion, allogeneic stem cell transfer and reconstitution of the bone marrow, HIV will not be able to replicate anymore in the new donor T-cells which carry chemokine receptor mutations such as CCR2-64I, CCR5-D32, or SDF1 -3'A.
  • the therapeutic TRC administration is preferably followed by allogeneic cell, e.g. stem cell, transplantation.
  • Suitable cells for transplantation are haematopoietic stem cells from allogeneic donors, which may be obtained by procedures as described in Karussis & Vaknin-Dembinsky (Expert Rev Clin Immunol 6 (2010), 347-352), Gratmple et al. (JAMA 303 (2010), 1617-1624), Alchalby & Kroger (Curr Hematol Malig Rep 5 (2010), 53-61 ), Pessina et al. (Cell Biol Int (2010) Apr 16 Epub), Cerdan & Bhatia (Int J Dev Biol (2010) Mar 15 Epub), Bueno et al. (Stem Cell Rev (2010) Feb 24 Epub), Jing et al.
  • allogeneic stem cells may be derived from umbilical cord blood and expanded in vitro using suitable ligands, e.g. peptide or peptide-derived ligands.
  • suitable ligands e.g. peptide or peptide-derived ligands.
  • autologous stem cells may be transplanted.
  • Autologous stem cells may be derived from the bone marrow. They may be used after expansion or without expansion.
  • the radionuclide of the TRC may be a therapeutically effective radionuclide, i.e. a radionuclide which is suitable for the treatment of haematological malignant disorders by irradiation, preferentially a ⁇ -emitter.
  • the therapeutically effective radionuclide may be yttrium-90 ( 90 Y), iodine-131 ( 131 l), samarium-153 ( 53 Sm), holmium-166 ( 166 Ho), rhenium-186 ( 186 Re), rhenium-188 ( 188 Re) or another ⁇ - or ⁇ / ⁇ -emitting radionuclide, or may be an a-emitter such as astatine-21 1 ( 211 At), bismuth-212 ( 2 2 Bi), bismuth-213 ( 2 3 Bi) or actinium-225 ( 225 Ac).
  • a-emitter such as astatine-21 1 ( 211 At), bismuth-212 ( 2 2 Bi), bismuth-213 ( 2 3 Bi) or actinium-225 ( 225 Ac).
  • the therapy may additionally comprise administration of radionuclides suitable for imaging before therapeutic irradiation of bone marrow cells.
  • the radionuclide of the TRC may also be an imaging radionuclide, i.e. a radionuclide which is suitable for monitoring and/or determining pharmacokinetics of the TRC allowing dosimetry.
  • the imaging radionuclide may be a ⁇ -emitter such as indium-1 1 1 ( ln), iodine-131 ( 131 l) or techneticum-99m ( 99m Tc) or another ⁇ -emitter.
  • the invention encompasses determining the therapeutically effective dose of a therapeutic TRC prior to administration. This determination may be carried out individually for a subject to be treated, or for a group of subjects, e.g. based on the severity or progression of the disease.
  • the invention may comprise the administration of a TRC comprising an imaging radionuclide and a subsequent administration of a TRC comprising a therapeutically effective radionuclide.
  • the effective dose of the subsequently administered therapeutic TRC may be individually determined and/or adjusted for a respective subject, e.g. a human patient.
  • the CD66-binding component of the imaging TRC and the therapeutic TRC is preferably identical, at least with respect to the CD66- binding specificity and/or affinity.
  • a further preferred embodiment of the invention comprises determining a therapeutically effective dose of a TRC by evaluating pre-existing data, e.g. from a database.
  • bone marrow biopsies can be used to estimate the patients' bone marrow to predict its eligibility for therapeutic TRC.
  • the CD66-binding component is preferably a polypeptide comprising at least one antibody binding domain, for example an antibody, particularly a monoclonal antibody, a chimeric antibody, a humanized antibody, a recombinant antibody, such as a single chain antibody or fragment thereof, e.g. proteolytic antibody fragments such as Fab-, Fab'- or F(ab) 2 -fragments or recombinant antibody fragments, such as single chain Fv-fragments.
  • the CD66-binding component may also be a fusion polypeptide comprising at least one antibody binding domain and a further domain, e.g. an effector domain such as an enzyme or cytokine.
  • the CD66-binding molecule may be an artificial binder, e.g. a scaffold polypeptide, such as an ankyrin, an anticalin, a modified fibronectin III domain, a lipocalin, an ubiquitin, a modified protein A, a C-type lectin, a FYN SH3 domain, a camelid antibody, a cys-knot domain or another protein domain designed for ligand binding as described in Nature Biotech 23 (2005), 1493-1494, the content of which is herein incorporated by reference.
  • a scaffold polypeptide such as an ankyrin, an anticalin, a modified fibronectin III domain, a lipocalin, an ubiquitin, a modified protein A, a C-type lectin, a FYN SH3 domain, a camelid antibody, a cys-knot domain or another protein domain designed for ligand binding as described in Nature Biotech 23 (2005), 1493-1494, the content of which is herein
  • the CD66-binding component selectively binds to the human CD66 antigen or an epitope thereof, e.g. CD66a, b, c, or e.
  • the CD66-binding component is the BW250/183 antibody.
  • Murine, humanized and recombinant forms of this antibody are described in EP-A-0 388 914, EP-A-0 585 570 and EP-A-0 972 528, which are herein incorporated by reference.
  • the radionuclide is preferably linked to the CD66-binding component via a chelating agent, with the linkage preferably being a covalent linkage.
  • the CD66-binding component may be designated as targeted radioactive chelate. More preferably the radionuclide is linked to the CD66- binding component via a structure of the formula
  • n 1 to 15
  • p 0 or 1
  • R 1 and R 3 are independently selected from the group consisting of -NHCSNH-, -NHCONH-, -NHCOCH 2 S-, -S-S-, -NH-NH-, -NH-, -S-,
  • R 2 is selected from the group consisting of Ci-Ci 8 alkylene, branched Ci-Ci 8 , -CH 2 -C 6 H 10 -, p-alkylphenylene, p-phenylene, m-phenylene, p- alkyloxyphenylene, naphthylene, -[CH CH O] - , -[CH CH SOCH CH 1 -, - [CH 2 CH 2 S0 2 CH 2 CH 2 ] x -, or -[NHCHR 4 CO] y -, wherein x is 1 to 200, y is 1 to 20, and wherein R 4 is selected from the group consisting of H-, Me-, HSCH 2 -, isopropyl, but-2-yl, CH 3 SCH 2 CH 2 -, benzyl, 1 H-indol-3-yl-methyl, HOCH 2 -, HOOCCH 2 -, CH 3 CH(OH)-, HOOCCH 2 CH 2
  • the chelating agent may be selected from the group consisting of diethylenetriaminepentaacetic acid (DTPA), 1 ,4,7, 10- tetraazacyclododecane-N,N ' ,N “ ,N “ ' -tetraacetic acid (DOTA), 1 ,4,8, 1 1 - tetraazacyclotetradecane-N,N ' ,N “ ,N “ ' -tetraacetic acid (TETA), 1 ,4,7- triazonane-N,N ' ,N “ -triacetic acid (NOTA), 2,2'-(2-(((1 S,2S)-2- (bis(carboxymethyl)amino)cyclohexyl)-
  • DTPA diethylenetriaminepentaacetic acid
  • DOTA 10- tetraazacyclododecane-N,N ' ,N “ ,N “ ' -tetraacetic acid
  • TETA 1
  • the administration of the therapeutic TRC for the treatment of human patients may be in a dose of > about 10 MBq/kg body weight (bw), of > about 15 MBq/kg bw, of > about 20MBq/kg bw, of > about 25 MBq/kg bw, of > about 30 MBq/kg bw or of > about 35 MBq/kg bw.
  • the TRC may be administered according to known methods, e.g. by infusion.
  • the inventors have found that at a dose of 25 MBq/kg the peripheral blood cells were already strongly reduced indicating that the stem cells in the bone marrow which produce the haematopoietic cells were already deleted.
  • a dose of about 20 MBq/kg to about 30 MBq/kg is suitable.
  • the dose may be up to 45 MBq/kg.
  • Cell transplantation may comprise autologous or allogeneic stem cell transplantation.
  • Allogeneic stem cells may be derived from allogeneic donors or from cord blood of newborns after expansion in vitro using peptide-derived ligands to eliminate alloreactive T-cells.
  • Autologous stem cells may be derived from the patient's bone marrow.
  • Preferred therapeutic protocols of the invention comprise the steps:
  • the imaging TRC is preferably an indium-1 1 1 labelled anti-CD66 antibody or artificial binder.
  • the therapeutic TRC is preferably an yttrium-90 labelled anti-CD66 antibody or artificial binder.
  • the protocols do not comprise administration of an anti-tumor agent such as melphalan and/or administration of an immunosuppressive agent at least 10, 15 or 20 days before and/or after therapeutic TRC administration and/or in the period between administration of therapeutic TRC and cell transplantation.
  • an anti-tumor agent such as melphalan
  • an immunosuppressive agent at least 10, 15 or 20 days before and/or after therapeutic TRC administration and/or in the period between administration of therapeutic TRC and cell transplantation.
  • the therapeutic protocols of the invention consist of the following steps:

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Developmental Biology & Embryology (AREA)
  • Engineering & Computer Science (AREA)
  • Cell Biology (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Mycology (AREA)
  • Hematology (AREA)
  • Reproductive Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biotechnology (AREA)
  • Virology (AREA)
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  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne l'utilisation de composés radioactifs ciblés (TRC) pour le traitement de troubles inflammatoires et/ou auto-immuns, ainsi que de troubles immunosuppresseurs.
PCT/EP2011/058274 2010-05-20 2011-05-20 Composé radioactif ciblé pour cd66 humain pour le traitement de troubles WO2011144744A1 (fr)

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US34661910P 2010-05-20 2010-05-20
US61/346619 2010-05-20

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3351271A1 (fr) 2017-01-23 2018-07-25 TheraPharm GmbH Radioimmunoconjugué destiné à être utilisé dans le traitement de maladies associées à la moelle osseuse

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3351271A1 (fr) 2017-01-23 2018-07-25 TheraPharm GmbH Radioimmunoconjugué destiné à être utilisé dans le traitement de maladies associées à la moelle osseuse
WO2018134430A1 (fr) 2017-01-23 2018-07-26 Therapharm Gmbh Radioimmunoconjugué destiné à être utilisé dans le traitement de maladies associées à la moelle osseuse
CN110167603A (zh) * 2017-01-23 2019-08-23 塞拉法尔目有限责任公司 用于治疗骨髓相关疾病用途的放射性免疫缀合物
AU2018209794B2 (en) * 2017-01-23 2020-02-06 Therapharm Gmbh Radioimmunoconjugate for use in treating bone marrow associated diseases
JP2020505462A (ja) * 2017-01-23 2020-02-20 テラファーム ゲー・エム・ベー・ハーＴｈｅｒａＰｈａｒｍ ＧｍｂＨ 骨髄関連疾患の治療に使用するための放射性免疫複合体

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