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WO2012000863A1 - Complexe contenant un aptamère pour la détection d'un tissu malade - Google Patents

Complexe contenant un aptamère pour la détection d'un tissu malade Download PDF

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Publication number
WO2012000863A1
WO2012000863A1 PCT/EP2011/060430 EP2011060430W WO2012000863A1 WO 2012000863 A1 WO2012000863 A1 WO 2012000863A1 EP 2011060430 W EP2011060430 W EP 2011060430W WO 2012000863 A1 WO2012000863 A1 WO 2012000863A1
Authority
WO
WIPO (PCT)
Prior art keywords
aptamer
complex
chemical element
diseased tissue
biomolecule
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.)
Ceased
Application number
PCT/EP2011/060430
Other languages
German (de)
English (en)
Inventor
Hartmuth C. Kolb
Ursus KRÜGER
Oliver Lade
Arno Steckenborn
Tanja Weil
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.)
Siemens AG
Max Planck Gesellschaft zur Foerderung der Wissenschaften
Siemens Corp
Original Assignee
Siemens AG
Max Planck Gesellschaft zur Foerderung der Wissenschaften
Siemens Corp
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 Siemens AG, Max Planck Gesellschaft zur Foerderung der Wissenschaften, Siemens Corp filed Critical Siemens AG
Publication of WO2012000863A1 publication Critical patent/WO2012000863A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • 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
    • A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
    • A61K51/065—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules conjugates with carriers being macromolecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems

Definitions

  • Aptamer complex for detection of a diseased tissue The invention relates to the use of a complex umfas ⁇ send an aptamer and a biomolecule for the production of an agent for detecting a diseased tissue. It further relates to a diagnostic for localizing a diseased tissue comprising such a complex.
  • biochemical analyzes of blood, other body fluids and tissue samples are used to characterize diseases. It examines the presence and amount of molecules that are typical of a particular disease. In addition to foreign substances also endogenous substances are detected, which are ⁇ example, only formed in an infection by viruses or bacteria.
  • tumor cells frequently form large amounts of certain proteins, in particular cellular receptors whose expression is specific for a type of tumor.
  • proteins that are made specifically from diseased cells are surface molecules that are anchored in the membrane which he ⁇ diseased cells. These surface molecules can be detected by appropriate diagnostic procedures. For this purpose, usually cells from tissue or blood samples are examined with antibodies that bind to specific disease-specific surface molecules. Such in vitro studies can diagnose the presence of a disease.
  • ectopic cell aggregates such as tumors or swellings of individual organs, can be used with them. locate gane.
  • a diseased tissue shows no marked morphological abnormalities, or is relatively small, it can easily be overlooked in traditional studies.
  • the invention is therefore based on the object, an agent be ⁇ riding determine by which a diseased tissue can be specifically and regardless of its size detected.
  • This object is achieved by the use of a complex of formula I:
  • A is an aptamer
  • V is missing, or is a linker molecule
  • B is a biomolecule, to produce an agent for the detection of a diseased tissue.
  • the biomolecule binds to the diseased tissue and the aptamer is bound to a detectable chemical Ele ⁇ ment, a few cells of a diseased tissue with reference to the detectable signal of the chemical element can be localized itself.
  • aptamer refers to short, single-stranded nucleic lein Textre oligomers that can accommodate both RNA and DNA molecules to ⁇ . Depending on their respective sequence, aptamers form diverse structures and bind to target molecules of the most diverse classes of substances. This results in a specific structural compatibility between an aptamer and its target molecule, similar to antigen-antibody binding. The structural compatibility of the molecules takes place via electrostatic interactions, ionic binding, van der Waals interactions, hydrogen bonding and so-called stacking interactions between the aromatic rings of the bases of the nucleic acids.
  • Aptamers that bind a specific target molecule are generated by in vitro selection and amplification techniques, so-called SELEX processes (Systematic Evolution of Ligands by Exponential Enrichment).
  • Aptamers comprise regularly 8-220 nucleic ⁇ otide, preferably 20 to 60 nucleotides. However, it is also possible to use aptamers with up to 500 nucleotides. They can be produced synthetically or obtained by enzymatic degradation of genomic DNA (Kulbachinskiy AV, 2007).
  • aptamers can be identified that bind to a specific target molecule. This can be both larger biomolecules, such as proteins, as well as to individual chemical ele ⁇ ments.
  • detecttable chemical element encompasses the chemical elements that can be detected by their radioactive or luminescent radiation or their magnetic moment. These include, but are not limited to, 68 gallium, gadolinium, europium 2+ , europium 3+ terbium 3+, and 64 copper. Aptamers that specifically bind to one of these elements are isolated from aptamer libraries using Selex methods. They can then be detected by the radiation or the paramagnetism of their bound chemical element.
  • biomolecule includes molecules of biological origin or are made up of natural ingredients and have the ability to specifically interact with other Mole ⁇ cules and retain them. Each cell carries on its surface, anchored in its cell membrane, a multitude of different molecules, most of which belong to the class of proteins.
  • the biomolecule binds to the diseased tissue.
  • the biomolecule is selected so that the Bin ⁇ connection between the biomolecule and the target molecule on the surface of the diseased tissue is a linear Koeffi ⁇ coefficient called. KD value of ⁇ 100 nM, preferably ⁇ 10 nM, most preferably of 7.5 nM.
  • diseased tissue refers to cells, parts of organs or whole organs that do not or not fully fulfill their physiological function. These include, for example, viruses or bacteria infected cells, hypertrophic tissue, inflamed tissue and organs, hyperplasti ⁇ MOORISH and neoplastic tissue, such as ulcers, tumors and cancers. Diseased cells often form proteins whose expression is indicative of a particular disease, for example, because they are derived from the genetic material of a virus or bacterium. When these molecules are cell surface molecules, they are anchored to the cell membrane. By the biomolecule specially
  • connecting molecule includes chemical compounds that are capable of linking two individual chemical molecules to form a stable complex.
  • the aptamer is bound to a detectable che ⁇ premix element, linked to the biomolecule, which in turn binds specifically to the pathological tissue.
  • Suitable linker molecules include other branched and unbranched alkyls and alkenes, and aldehydes, which can carry amino groups gege ⁇ appropriate, additionally.
  • the resulting complex is a patient verab ranges ⁇ , is deposited in the body to the diseased tissue and can via the detectable chemical element nachge ⁇ recognized and localized. This makes it possible to detect even a few cells of a diseased tissue.
  • An advantage of complexing a biomolecule with an aptamer bound to a detectable chemical element is that none of the usual complexing agents, such as diethylenetriamine pentaacetate (DTPA), 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA) used ⁇ who must to provide the biomolecule with a marker.
  • DTPA diethylenetriamine pentaacetate
  • DOSA 1, 4, 7, 10-tetraazacyclododecane-1
  • DOTA diethylenetriamine pentaacetate
  • DOTA 1, 4, 7, 10-tetraazacyclododecane-1
  • DOTA tetraacetic acid
  • the complex lies in the favorable signal / background ratio during detection.
  • the biomolecule Through the biomolecule, the complex binds to the diseased tissue, whereas free, unbound complexes are rapidly metabolized and excreted from the organism because they are rapidly degraded by endogenous enzymes. This creates a strong and specific signal at the position of krankhaf ⁇ th tissue and the background signal is minimized.
  • the detectable chemical element is a radioactive, paramagnetic or fluorescent chemical element ⁇ table. For the detection of such elements, established methods and devices are available. The agent for detection of a diseased tissue can therefore be used immediately without adding any new process or equipment designed for the detection or be ⁇ manages must be.
  • Radioactive elements such as crizos- 11 or 68 carbon gallium are detected by Szintigra ⁇ chromatography, Single Photon Emission Computed Tomography (SPECT) or positron emission tomography (PET).
  • PET is an established method for detecting the radiation of radioactive elements and determining their position (Massoud TF, Gambhir SS, 2003). With the aid of detector devices arranged annularly around the patient, sectional images are created on which the decay events are represented in their spatial distribution in the interior of the body. PET also makes it possible to quantify the amount of labeled molecules in a tissue.
  • Paramagnetic elements such as gadolinium (Gd) are detected by Magnetreso ⁇ resonance imaging (MRI), wherein it also is a long-used in the medical procedure.
  • MRI Magnetreso ⁇ resonance imaging
  • the biomolecule is selected from the group consisting of peptides, aptamers, micro-antibodies and receptor ligands. These molecules are capable of specifically binding surface molecules of a diseased tissue. They are also composed of endogenous components, nucleic acids or amino acids, which makes them particularly well tolerated.
  • Both peptides and aptamers can be selected to bind a particular surface molecule of diseased tissue.
  • an increasing number of micro-antibodies are available that are directed against disease-specific molecules. This can be linked to an aptamer that binds a detectable chemical element who ⁇ .
  • Receptor ligands are particularly suitable for detecting tumors because tumor cells often express large amounts of specific receptors on their cell surface.
  • Another object of the invention is a diagnostic for the localization of a diseased tissue comprising a complex of the formula I: A - V - B.
  • the Diagnosti ⁇ kum is suitable to detect even a few cells of a diseased tissue.
  • the he ⁇ inventive diagnostic agent offers, by the advantages of the complex contained, a sensitive and well-tolerated agent to the position of a diseased tissue in vivo determine.
  • the diagnostic agent is administered to the patient, and the complexes contained therein are rapidly and efficiently distributed in the body because of their small size. They bind to the diseased tissue and collect on its surface.
  • the accumulation of the complexes is, according to the chemical element bound to the aptamer, observed by means of PET, MRI or optical devices and thus determines the exact Posi ⁇ tion of the diseased tissue in the body of the patient.
  • the detectable chemical element is a radioactive or para ⁇ magnetic chemical element.
  • a diagnostic agent that has a complex whose aptamer is bound to a radioactive or paramagnetic chemical element is particularly suitable for pre- and postoperative investigations. In addition to the position, the size and extent of a diseased tissue can be displayed.
  • the diagnostic agent comprises a further complex of formula I: A - V - B, in which the aptamer is bound to a fluorescent chemical Ele ⁇ ment.
  • the diagnostic agent can be designed so that both complexes are administered simultaneously or separately, for example in separate doses to the patient.
  • the radioactive dose of the diagnostic agent is then used in the preoperative stage to the diseased tissue ⁇ taping the patient's body to Loka.
  • the fluorescent dose is used later to the diseased tissue visible to ma ⁇ chen during the procedure. This allows visual monitoring of whether all marking Diseased cells are removed from the body. After the operation can be checked with a radioactive or paramagnetic complex, again whether krankhaf ⁇ th cell retarded or in the organism are grown.
  • the fact that the biomolecule of the complexes used is always identical ensures that the same pathogenic cells are always detected, regardless of which detection method is used.
  • Another object of the invention is a complex of formula I:
  • A is an aptamer
  • V is missing, or is a linker molecule
  • B is a biomolecule.
  • the biomolecule of the complex binds to a specific tissue ⁇ be and the aptamer is bound to a detectable chemical ele ⁇ ment.
  • This complex is particularly suitable for detecting pathological tissue, but can also be used to localize healthy cells.
  • the organic molecule is selected so that it binds to a molecule that characterize ⁇ drawing for to be detected cells.
  • Another object of the invention is an aptamer that binds a detectable chemical element.
  • various imaging modalities are used in medicine, especially X-ray, PET and MRI.
  • special tracers are also used, which accumulate more frequently in tumor tissue, for example.
  • These tracers predominantly sugar molecules and other metabolic products, have hitherto been linked to detectable elements via chemically complex chelator molecules.
  • the resulting complexes are poorly tolerated by patients and remain in the body for a particularly long time because they are not degraded by endogenous mechanisms. you can.
  • the aptamer according to the invention is composed of endogenous building blocks, namely nucleic acids, and is therefore well tolerated and metabolizable. It can be bound by simple molecular connections to any molecules that serve as tracers or as specific detection molecules.
  • the detectable chemical element is selected from the group consisting of 68 gallium, gadolinium, europium 2+ , europium 3+ terbium 3+ and 64 copper. Aptamers that are ge ⁇ connected to one of these elements are particularly advantageous, since these elements can be detected with established methods of detection.
  • a method for localizing a diseased tissue in an organism comprising
  • the organic ⁇ molecule binds to the pathological tissue, and the aptamer is bound to a detectable chemical element.
  • FIG. 1 schematically shows a complex 1 comprising an aptamer 2 and a biomolecule 3, which are linked via a connecting molecule 5.
  • the aptamer 2 is bound to a detectable chemical element 4, namely a 68 gallium.
  • the 68 gallium is represented by an asterisk (*).
  • the diseased tissue 18 forms a cell surface receptor 6 indicative of the disease of the tissue.
  • a biomolecule 3 is selected which binds to Zellober perennialrezep ⁇ tors. 6
  • the biomolecule 3 is linked via a connecting molecule 5 with the aptamer 2, which is bound to the 68 gallium.
  • the gallium in the decay of 68 give ⁇ added positrons are detected by positron emission tomography (PET).
  • PET positron emission tomography
  • Complex 1 is administered to a patient in the form of a Arzneimit ⁇ means of, binds to the diseased tissue 18 and sam ⁇ melt at its cells. This accumulation becomes visible in a positron emission tomography (PET), so that the Distribution of the complex 1 or the position of the diseased tissue 18 in the body of the patient can be determined.
  • PET positron emission tomography
  • FIG. 2 shows a schematic illustration (greatly simplified according to Faller A, Schünke M, The body of man,
  • the circulation system 10 includes various organs schematically represented, such as the lungs 12, heart 13, liver 14, 15 intestine and kidney 16 and the main wires 11 which these organs ver ⁇ bind.
  • the complex 1 is represented by triangles along the wires 11.
  • the degradation products 17 of the complex 1 are represented by individual lines within the outline of the kidney 16.
  • Left of center of the circulatory system 10 is additionally ⁇ a diseased tissue 18, for example, a tumor or an inflammation, shown, are attached to the increased complexes.
  • the distribution of complex 1 in the circulatory system 10 includes four phases listed along the top-to-bottom illustration.
  • Phase I Complex 1 is injected into the circulatory system 10 of the organism.
  • Phase II the blood circulatory system 10 of the Complex 1 in the organs 12, ⁇ 13, 14, 15, and 16 of the body transported advantage.
  • Phase III The circulating complex 1 binds specifically to the diseased tissue 18.
  • Phase IV Unbound complexes 1 are rapidly metabolised and enzymatically degraded. The organism not failed ⁇ det between the body's own molecules and the complex 1, because it is constructed from similar ingredients. The degradation products 17 of complex 1 accumulate predominantly in the kidney 16, from where they are excreted via the bladder and the ureter.
  • Massoud TF, Gambhir SS Molecular imaging in living subjects: seeing fundamental biological processes in a new light; Genes Dev. 2003 Mar 1; 17 (5): 545-80.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Physics & Mathematics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne un complexe (1) et son utilisation pour produire un agent de détection d'un tissu malade (18). Ce complexe (1) est de formule I: A - V - B, dans laquelle A désigne un aptamère (2), V manque ou représente une molécule de liaison (5), et B représente une biomolécule (3). Selon l'invention, la biomolécule (3) se lie au tissu malade (18) et l'aptamère (2) est lié à un élément chimique (4) détectable. L'invention porte également sur un agent de diagnostic destiné à la localisation d'un tissu malade (18) et comportant un complexe (1) de ce type.
PCT/EP2011/060430 2010-06-30 2011-06-22 Complexe contenant un aptamère pour la détection d'un tissu malade Ceased WO2012000863A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE201010026062 DE102010026062A1 (de) 2010-06-30 2010-06-30 Aptamer-Komplex zur Detektion eines krankhaften Gewebes
DE102010026062.2 2010-06-30

Publications (1)

Publication Number Publication Date
WO2012000863A1 true WO2012000863A1 (fr) 2012-01-05

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WO (1) WO2012000863A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1897562A1 (fr) * 2006-09-08 2008-03-12 Bayer Schering Pharma Aktiengesellschaft Aptaméres marquées avec Gallium-68
WO2008028530A1 (fr) * 2006-09-08 2008-03-13 Bayer Schering Pharma Aktiengesellschaft Composés sous forme d'aptamère-dimères et utilisations de ces composés dans le cadre d'un diagnostic et d'un traitement

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100183504A1 (en) * 2007-06-14 2010-07-22 Fanqing Frank Chen Multimodal imaging probes for in vivo targeted and non-targeted imaging and therapeutics

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1897562A1 (fr) * 2006-09-08 2008-03-12 Bayer Schering Pharma Aktiengesellschaft Aptaméres marquées avec Gallium-68
WO2008028530A1 (fr) * 2006-09-08 2008-03-13 Bayer Schering Pharma Aktiengesellschaft Composés sous forme d'aptamère-dimères et utilisations de ces composés dans le cadre d'un diagnostic et d'un traitement

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
FALLER A, SCHÜNKE M: "Der Körper des Menschen", 2008, THIEME-VERLAG
KULBACHINSKIY AV: "Methods for selection of aptamers to protein targets", BIOCHEMISTRY (MOSC), vol. 72, no. 13, December 2007 (2007-12-01), pages 1505 - 18, XP002593035, DOI: doi:10.1134/S000629790713007X
MASSOUD TF, GAMBHIR SS: "Molecular imaging in living subjects: seeing fundamental biological processes in a new light", GENES DEV., vol. 17, no. 5, 1 March 2003 (2003-03-01), pages 545 - 80, XP007905304, DOI: doi:10.1101/gad.1047403

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DE102010026062A1 (de) 2012-01-05

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