EP2015772A2 - Agent de traitement de pathologies malignes - Google Patents

Agent de traitement de pathologies malignes

Info

Publication number
EP2015772A2
EP2015772A2 EP07724827A EP07724827A EP2015772A2 EP 2015772 A2 EP2015772 A2 EP 2015772A2 EP 07724827 A EP07724827 A EP 07724827A EP 07724827 A EP07724827 A EP 07724827A EP 2015772 A2 EP2015772 A2 EP 2015772A2
Authority
EP
European Patent Office
Prior art keywords
bat3
tumor
cells
protein
malignant diseases
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Withdrawn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
EP07724827A
Other languages
German (de)
English (en)
Inventor
Elke Pogge Von Strandmann
Andreas Engert
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.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP2015772A2 publication Critical patent/EP2015772A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K39/0005—Vertebrate antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/15—Natural-killer [NK] cells; Natural-killer T [NKT] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/428—Undefined tumor antigens, e.g. tumor lysate or antigens targeted by cells isolated from tumor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0646—Natural killers cells [NK], NKT cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the cancer treated
    • A61K2239/56—Kidney
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the cancer treated
    • A61K2239/57—Skin; melanoma
    • 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 invention relates to an agent for the treatment of tumor diseases, autoimmune diseases or for use in cellular immunotherapy in the context of allogeneic and autologous transplants by activation or inhibition of BAT3 with a physiologically effective amount of the protein BAT3 (HLA-associated transcript 3) and / or BAT3 in conjunction with a tumor-specific antibody fragment, the DNA (cDNA) and / or RNA coding for the production of such an agent in the case of activation of the BAT3-dependent disease. Furthermore, the invention relates to the use of BAT3 cDNA for ex vivo and in vivo overexpression of BAT3 in tumor cells after viral or non-viral gene transfer, with the aim of eliciting an anti-tumor immune response in tumor patients.
  • a means of inhibiting or activating BAT3 by antagonistic or agonistic antibodies, antisense nucleotides or specific inhibitors By and large, a means of inhibiting or activating BAT3 by antagonistic or agonistic antibodies, antisense nucleotides or specific inhibitors. Furthermore, a diagnostic marker, such as a specific antibody for the diagnosis of the disease and for the follow-up.
  • the invention relates to an agent for the treatment of human diseases using the recombinant protein BAT3, the coding DNA / RNA, an inhibitor / activator of BAT3 in the form of
  • the invention relates to the use of the BAT3 cDNA for ex vivo and in vivo overexpression of BAT3 in human tumor cells after viral or non-viral gene transfer to achieve an NKp30-mediated immune response against the tumor cells in human malignant diseases.
  • NK cells which as a component of the innate immune system recognize malignant cells, combat them directly and contribute to the formation of an adaptive immune response against the tumor cells, have recently been increasingly used for the immunotherapy of malignant diseases.
  • NK cells against tumor cells are controlled via activating receptors, which include the natural cytotoxic receptors (NCRs) with the important NKp30.
  • the stimulation of the receptors, as well as that of NKp30, is based on the interaction with the corresponding ligands on malignant cells and leads to the lysis of the target cells (Pende, D., et al., J Exp Med 190, 1505 (Nov 15, 1999)).
  • the ligand (or possibly the ligands) of NKp30 is basically suitable for tumor therapy. So far, however, the cellular ligand has been described only indirectly with the aid of masking antibodies, and the molecular identification of the ligand was still pending (L. Moretta, A.
  • NKp30 is a membrane protein of tumor cells
  • a nuclear protein as a cellular ligand of the NKp30 receptor.
  • BAT3 the first cellular tumor-associated ligand of the surface receptor NKp30, one of the important activating immune receptors of NK cells.
  • this nuclear protein arrives at the surface of the cells and is also released from the cells as soon as the cells receive a "stress signal.” This may be a heat shock or contact with NK cells.
  • BAT3 may lead to inhibition or activation of NK cells, which is mainly mediated through the Natural Cytotoxicity Receptors (NCRs).
  • NCRs Natural Cytotoxicity Receptors
  • BAT3 can lead to activation (cytotoxicity, cytokine secretion) on the cell surface or associated with exosomes in the supernatant of tumor cells.
  • the recombinant, purified protein inhibits NK cell activity.
  • the addition of BAT3-specific cross-linking antibodies in combination with purified BAT3 leads to a dramatic increase in NK cell activity.
  • NKp30, NCR NKp30, NCR
  • BAT3 nuclear protein
  • NKp30-specific ligands on tumor cells correlates directly with their sensitivity to NK cells, so that the loss of ligands represents a strategy of the tumor cells to escape control by the immune system.
  • NKp30 not only applies to NKp30, but also to the already known ligands of a second activating receptor of NK cells, the NKG2D receptor.
  • Genherapeutic pre-clinical data are already available, showing that the overexpression of NKG2D ligands leads to the successful control of the corresponding tumor by the immune system.
  • This activation is independent of the activity of the inhibiting NK receptors, which normally prevent NK cells from attacking the body's own cells (eg A. Cerwenka, JL Baron, LL Lanier, Proc Natl Acad. USA 98, 11521 (Sep 25, 2001 A. Diefenbach, ER Jensen, AM Jamieson, DH Raulet, Nat ⁇ re 413, 165 (Sep 13, 2001)).
  • NKG2D ligand-based recombinant constructs also show promising anti-tumoral activity, as has been demonstrated in various preclinical studies (Germain, C. et al., Clin Cancer Res 11, 7516 (Oct. 15, 2005); E. Pogge, Strandmann et al., Blood (Oct 6, 2005)).
  • Our identification of BAT3 as a cellular ligand of NKp30 and our studies on the function of BAT3 show that this new ligand BAT3 is suitable for tumor therapy targeting NKp30 / NCR-mediated NK cell stimulation.
  • the invention therefore also provides an agent for the treatment of patients with malignant diseases, in which a physiologically effective amount of the protein BAT3 is contained as active ingredient in a pharmaceutically acceptable carrier material.
  • BAT3 in tumor therapy is the use as a fusion protein with an antibody fragment that binds specifically to
  • a BAT3 / anti-CD138 is to be used therapeutically to support an anti-tumor immune response in patients with multiple myeloma, similar to that already described for the bispecific
  • CD138 Protein ULBP2 / CD138 (Pogge et al., 2006).
  • the used B-B4 single chain antibody fragment with specificity for CD138 (Syndecan 1) is basically very well suited for this application.
  • CD138 is a member of Syndecan family, heparan sulfate proteoglycans, play a role in cell adhesion, differentiation and proliferation and are often overexpressed on malignant multiple myeloma cells while lacking on other hematopoietic cells (Dhodapkar MV, Sanderson RD et al., Leuk Lymphoma 1999; 34: 35-43).
  • Another example is the inhibition of BAT3 in autoimmune diseases to modulate a hyperreactive immune system.
  • Antagonist and agonistic BAT3-specific antibodies and recombinantly produced BAT3 protein can be used for the therapy of malignant diseases and immunological diseases.
  • NK cells activation of NK cells in the context of cellular immunotherapy by recombinant BAT3 or derivatives / antibodies within the culture phase of these cells before transplantation, as well as systemic administration after transplantation, is a novel approach that improves therapy.
  • Another example is the diagnosis of diseases and therapy by detecting BAT3 on the cells and in the serum. This can be done by antibody-based techniques, for example ELISA, Fig. 2), but also other specific detection methods.
  • the invention thus relates to an agent for the treatment of patients with multiple myeloma, in which a physiologically effective amount of the protein BAT3 / antiCD138 or BAT3 and derivatives of BAT3 or BAT3-specific antibodies is contained as active ingredient in a pharmaceutically acceptable carrier material.
  • a physiologically effective amount of the protein BAT3 / antiCD138 or BAT3 and derivatives of BAT3 or BAT3-specific antibodies is contained as active ingredient in a pharmaceutically acceptable carrier material.
  • Other possible uses are malignant diseases and immunological diseases (allergies, autoimmune diseases).
  • the agent according to the invention contains the anti-tumor immune response modulating protein BAT3 and derivatives of BAT3, BAT3 / antiCD138 fusion constructs or BAT3-specific antibodies as active ingredient for the therapy and diagnosis of malignant diseases and for the modulation of the immune system.
  • the agent of the invention for the treatment of malignant diseases contains the active ingredient in a conventional pharmaceutically acceptable and acceptable carrier material. It may be useful to administer the drug systemically, as it is known for example in the interferon therapy of multiple sclerosis or for the treatment of diabetes.
  • the protein or the DNA and / or RNA coding for it or the specific BAT3 antibodies can be stabilized for storage and for the prevention of premature reduction of activity. Stabilization can be achieved by incorporation of conventional additives, e.g. Buffer substances, salts of other proteins as well as DNA and RNA can be achieved. Examples are albumin, herring sperm, DNA, tRNA and detergents such as Triton, alkali and alkaline earth ions and the like. Storage of the agent and / or active ingredient in dried or freeze-dried form or after
  • Shock freezing in liquid nitrogen may also be useful.
  • the agent according to the invention may of course contain the active ingredient in modified form, i. as a protein in which individual amino acids are exchanged or missing.
  • the prerequisite is that the thus-modified active substance still provides the effect it requires in stimulating the immune effector cells for the treatment of patients with malignant diseases.
  • Reasons for such modifications may be the stabilization of the active ingredient, technical or formulation-technical reasons or also an improvement of the effect or the spectrum of action. In question are mutation and fusion after chemical or genetic engineering
  • the protein can be obtained in a conventional manner after cloning the gene into suitable vectors recombinant from bacteria or eukaryotes according to standard methods.
  • the agent according to the invention for the treatment of malignant diseases by the activation of the immune effector cells contains the active ingredient in a pharmaceutically acceptable carrier material, which on the one hand can consist of several conventional constituents.
  • the carrier material expediently contains a transfer medium suitable for the active ingredient.
  • the agent is intended primarily for systemic administration and ex vivo therapy in the context of cellular immunotherapies.
  • BAT3 cDNA for overexpression of BAT3 in tumor cells by viral and non-viral methods of gene transfer of the invention, since BAT3 overexpimating tumor cells are suitable, via the stimulation of NCR Receptors to support an NK cell-mediated anti-tumor immune response.
  • the invention is further illustrated by the following examples in which experimentally the effectiveness of BAT3 ligand is detected. For a further explanation of the examples and further examples, reference is made to the accompanying manuscript.
  • NK cells Increased cytotoxicity against tumor cells
  • NK cells isolated from the blood of healthy donors were used lo as effector cells in europium release assays.
  • Target cells human tumor cell lines labeled with europium and incubated with NK cells in the indicated devisequently, the amount of europium released is determined in the supernatant, which is used as a measure of the
  • NK-mediated cell lysis is used.
  • the value for a 100% lysis results after incubation of the cells with a detergent which leads to lysis.
  • the spontaneous lysis is taken into account, which is determined in batches without NK cells.
  • NK cells effector were incubated for the europium release assay in the ratios indicated with the human colon carcinoma line LS175T, which with an expression construct for BAT3 (BAT3) or the
  • BAT3 BAT3
  • CD3 ⁇ -BAT3-CT membrane-bound BAT3 5 derivative
  • control vectors without BAT3 cDNA were introduced into LS175T cells. After 36 hours, the tumor cells were mixed with primary NK cells from peripheral blood of healthy donors (see above) in the ratio 1: 1 and incubated for a further 48 hours.
  • the NK cells were previously stimulated overnight with interleukin 2 (10U) alone or in combination with interleukin 15 (10 ng ml -1 ) Interferon ⁇ in the supernatants were assayed for interferon g secretion of the NK cells using a IFN ⁇ ELISA kits (human interferon ⁇ ELISA Kit (R & D Systems)) .
  • IFN ⁇ ELISA kits human interferon ⁇ ELISA Kit (R & D Systems)
  • BAT3 upper part of the figure
  • BAT3 which is released from the tumor cells into the supernatant (detected in the i5 Western blot, see attached manuscript) and also that of a membranous variant (lower part of the figure) stimulates the interferon g secretion of NK cells (see Figure 2).
  • BAT3 is for the detection and elimination of tumors (multiple
  • Myeloma essential: in vivo experiment (mouse xenograft model)
  • mice Human multiple myeloma cells (line RPMI8226) were injected into nude mice. This leads to the formation of subcutaneous tumors in 8 out of 10 mice. The tumor volume on day 13 and day 20 is indicated (circles). If the mice additionally receive human peripheral blood lymphocytes (PBL), the tumor cells are eliminated and tumor formation does not occur in any case. In addition, the mice were given control antibodies (control antibodies) that do not interfere with tumor cell recognition (black cross). However, when the mice receive BAT3-specific antibodies that deplete the endogenous BAT3 protein, tumor cell recognition and elimination are inhibited (yellow triangles, tumors in 6 out of 10 mice).
  • control antibodies control antibodies

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Wood Science & Technology (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cell Biology (AREA)
  • Hematology (AREA)
  • Toxicology (AREA)
  • Mycology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • General Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

Agent de traitement de pathologies tumorales, telles que par exemple le myélome multiple, qui agit sur les cellules NK par l'activation d'une réponse immunitaire anti-tumorale aptès stimulation du récepteur NKp30 et des récepteurs de cytotoxicité naturelle (NCR). Il s'agit d'une quantité physiologiquement efficace de la protéine BAT3, BAT3/antiCD138 ou d'anticorps sécifiques de BAT3 ou de dérivés de ces produits, dans un excipient acceptable. En outre, la présente invention peut également être utilisée pour le traitement de tumeurs à négativité CD138 selon le principe identique de la protéine BAT3/antiCD138. A cet effet, la fraction antiCD138 avec un fragment d'anticorps est échangée contre un antigène tumoral quelconque et l'agent correspondant est utilisé pour la thérapie de tumeurs qui expriment cet antigène tumoral. La présente invention concerne encore l'utilisation de protéine BAT3 de recombinaison ou d'un fragment de BAT3 sans fraction de fusion basée sur les anticorps pour traiter des pathologies malignes par l'activation de NKp30 et NCR sur des cellules NK. La présente invention concerne enfin l'utilisation de l'ADNc BAT3 pour l'introduction in vivo et / ou ex vivo de BAT3 dans des cellules tumorales qui entraîne une meilleure reconnaissance par les cellules NK, pour la térapie immunitaire de pathologies malignes.
EP07724827A 2006-05-03 2007-05-03 Agent de traitement de pathologies malignes Withdrawn EP2015772A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102006020317 2006-05-03
DE102006028893 2006-06-21
PCT/EP2007/003901 WO2007144046A2 (fr) 2006-05-03 2007-05-03 Agent de traitement de pathologies malignes

Publications (1)

Publication Number Publication Date
EP2015772A2 true EP2015772A2 (fr) 2009-01-21

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Family Applications (1)

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EP07724827A Withdrawn EP2015772A2 (fr) 2006-05-03 2007-05-03 Agent de traitement de pathologies malignes

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US (1) US20100291105A1 (fr)
EP (1) EP2015772A2 (fr)
WO (1) WO2007144046A2 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009080831A1 (fr) 2007-12-26 2009-07-02 Biotest Ag Procédé permettant de réduire les effets secondaires cytotoxiques et d'améliorer l'efficacité des immunoconjugués
US9221914B2 (en) 2007-12-26 2015-12-29 Biotest Ag Agents targeting CD138 and uses thereof
CN101965366B (zh) * 2007-12-26 2016-04-27 生物测试股份公司 靶向cd138的免疫缀合物及其应用
WO2009080832A1 (fr) * 2007-12-26 2009-07-02 Biotest Ag Procédés et agents permettant d'améliorer le ciblage de cellules tumorales exprimant cd138
AU2013201618B2 (en) * 2009-05-06 2016-06-02 Biotest Ag Uses of immunoconjugates targeting CD138
CA2761120A1 (fr) * 2009-05-06 2010-11-11 Biotest Ag Utilisations d'immunoconjugues ciblant l'antigene cd138
KR20140100571A (ko) 2011-12-08 2014-08-14 바이오테스트 아게 Ｃｄ１３８을 타겟팅하는 면역접합체의 용도
GB201216002D0 (en) 2012-09-07 2012-10-24 Deutsches Rheuma Forschungszentrum Berlin Drfz Compositions adn methods

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1140973A4 (fr) * 1998-12-22 2002-10-30 Myriad Genetics Inc Interactions proteine-proteine dans les troubles neurodegeneratifs
US20050112118A1 (en) * 1999-12-02 2005-05-26 Myriad Genetics, Incorporated Compositions and methods for treating inflammatory disorders

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007144046A2 *

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WO2007144046A2 (fr) 2007-12-21
WO2007144046A3 (fr) 2008-04-03
US20100291105A1 (en) 2010-11-18

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