WO2012000865A1 - Peptide marqué au 11c servant à détecter une tumeur exprimant un récepteur her2/neu - Google Patents

Peptide marqué au 11c servant à détecter une tumeur exprimant un récepteur her2/neu Download PDF

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Publication number
WO2012000865A1
WO2012000865A1 PCT/EP2011/060447 EP2011060447W WO2012000865A1 WO 2012000865 A1 WO2012000865 A1 WO 2012000865A1 EP 2011060447 W EP2011060447 W EP 2011060447W WO 2012000865 A1 WO2012000865 A1 WO 2012000865A1
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WO
WIPO (PCT)
Prior art keywords
peptide
her2
neu receptor
tumor
carbon atom
Prior art date
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PCT/EP2011/060447
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German (de)
English (en)
Inventor
Friedrich Herberg
Hartmuth C. Kolb
Ursus KRÜGER
Oliver Lade
Arno Steckenborn
Original Assignee
Siemens Aktiengesellschaft
Universität Kassel
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Application filed by Siemens Aktiengesellschaft, Universität Kassel filed Critical Siemens Aktiengesellschaft
Publication of WO2012000865A1 publication Critical patent/WO2012000865A1/fr

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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
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/531—Production of immunochemical test materials
    • G01N33/532—Production of labelled immunochemicals
    • G01N33/534—Production of labelled immunochemicals with radioactive label
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer

Definitions

  • the invention relates to the use of a peptide for the manufacture ⁇ position of an agent for detecting a tumor expressing a Her2 / neu receptor. It further relates to a radiopharmaceutical comprising such a peptide for the localization of a tumor expressing a Her2 / neu receptor.
  • tumor cells In addition to soluble substances that are released into body fluids, tumor cells also produce molecules that remain anchored to their cell surface. This is mainly to cell receptors, such as receptors of the epidermal growth factor, insulin-like growth factor or wax ⁇ tumshormons. On the basis of these surface molecules, a biochemical chemical detection of tumor cells in vivo by visualizing them using imaging techniques.
  • the Her2 / neu receptor also known as ErbB2 is expressed by a large number of different cancers. It belongs to the family of epidermal growth factor (EGF) receptors. Unlike other receptors of this family, the Her2 / neu receptor itself does not bind ligands, but forms heterodimers with other EGF receptors after they have been ligated. The Her2 / neu receptor thereby contributes to the enhancement of the, via the tyrosine kinase function of the EGF receptors mediated intracellular signal, which is triggered by the binding of the ligand.
  • EGF epidermal growth factor
  • Suitable ligands were radiolabeled so that they could be detected by scintigraphy / positron emission tomography (PET) in the patient's body.
  • PET scintigraphy / positron emission tomography
  • radionuclides via large chelator molecules, for example 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) (Smith-Jones PM et al., 2006).
  • DOTA 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
  • the invention is therefore based on the object, a cost-effective and well-tolerated for the patient agent for the detection of a tumor expressing a Her2 / neu receptor to provide.
  • This object is achieved by the use of a peptide for the production of an agent for detection of a tumor expressing a Her2 / neu receptor.
  • peptide refers to an organic compound of at least two amino acids linked via a peptide bond. It includes both oligopeptides of up to about ten amino acids, polypeptides up to about 50 Amino Text ⁇ ren and proteins of up to 150 amino acids, regardless of their primary, secondary or tertiary structure. In this case, both naturally occurring and biotechnologically or synthetically produced compounds are included.
  • the peptide used according to the invention is chosen so that it binds to the Her2 / neu receptor.
  • the peptides can be used to detect tumors that form the Her2 / neu receptor.
  • the peptide is chosen so that the Bin ⁇ connection between the peptide and the Her2 / neu receptor, a so-called lithium-linear coefficient. KD value of ⁇ 100 nM, preferably ⁇ 10 nM, most preferably of 7 , 5 nM.
  • the peptide itself is made of amino acids, that is constructed so that it is very well tolerated by the patient from venezue ⁇ nen or body similar molecules. It is non-toxic and can be naturally metabolized, broken down and excreted ⁇ to be.
  • tumor refers to a local increase in Vo ⁇ lumens of tissue, such as an inflammatory Anschwel- or a spontaneous, unrestrained new formation of cells. Tumor cells often express certain receptor molecules that sit on the cell surface and are bound by specific ligands. These receptors also belong
  • Her2 / neu receptors which are strongly expressed in breast cancers, among others. Many of the tumors expressing the Her2 / neu receptor show aggressively invasive behavior, resulting in a correspondingly unfavorable disease prognosis. In most cases, the extremely increased expression of the Her2 / neu receptor is due to amplification of the
  • Her2 / neu gene (c-erbB2) returned to tumor cells.
  • Tumor cells expressing Her2 / neu receptor can therefore be distinguished well from healthy tissue by means of the peptide used according to the invention, since the tumor cells carry substantially larger amounts of Her2 / neu receptors and therefore more
  • positrons also referred to as ⁇ + radiation
  • positrons hit an electron, they form two photons which move away from each other at an angle of 180 °, ie exactly in the opposite direction.
  • the photons can be detected and used to calculate the position of the positron emission, or of the 11 C carbon atom.
  • the Integra ⁇ tion of a C-11 carbon atom in the peptide used in the invention makes it possible to avoid the use of chemical, physi- perfremder substances.
  • Another advantage of the peptide directly labeled with X1 C lies in the favorable signal / background ratio during detection.
  • the peptide binds specifically to the Her2 / neu receptor and forms a stable complex with it. Free, unbound peptides, on the other hand, are rapidly metabolized and excreted from the organism because they can be rapidly degraded by endogenous enzymes. This creates a strong and specific signal at the position of the Her2 / neu receptor, and the background signal is minimized.
  • the peptide has at least one D-amino acid.
  • D-amino acid With the exception of glycine, amino acids have a chiral center at their alpha carbon atom and can therefore exist as configurational isomers, namely as the D or L amino acid.
  • Endogenous peptides and proteins are largely made up of amino acids in ⁇ L-configuration.
  • most natural proteases and peptidases work stereoselectively and mainly metabolize L-amino acids. Therefore, the degradation of D-amino acids by endogenous enzymes takes longer than that of L-amino acids. This fact can be used to predict the half-life of a protein or peptide.
  • the non-natural amino acids should be chosen so that the binding affinity of the peptide is not altered.
  • other chemical Mo ⁇ dischenen individual amino acids of the peptide are possible to influence the half-life of the peptide specifically.
  • the terminal amino group of the peptide can be replaced by an isonitrile group.
  • Such modes ⁇ fication reduces, mediated by the amino group, in ⁇ ter syndrome with proteolytic enzymes, without the bond between the peptide used in the invention and the
  • the agent is a radiopharmaceutical.
  • radiopharmaceuticals refers to medicines containing radionuclides whose radiation is used for diagnosis and therapy. The main applications are in oncology, Kar ⁇ ogy and neurology, as well as pharmaceutical research.
  • radionuclides gamma or beta-emitting nuclides, for example 133 xenon, "technetium, 68 gallium, and fluorine, used. They are usually attached via Kom ⁇ formers such as DOTA, DTPA or EDTA mono- or polysaccharides.
  • the nuclides are detected by scintigraphy, single photon emission com- puted tomography (SPECT) or positron emission tomography (PET), depending on the nature of their radiation.
  • SPECT single photon emission com- puted tomography
  • PET positron emission tomography
  • conventional radiopharmaceuticals can cause side effects such as anaphylactic or allergic Reaktio ⁇ nen, in the body of a patient.
  • the use of a peptide from the body's own amino acids reduces these
  • the tumor expresses increased levels of the Her2 / neu receptor.
  • the cells of different tumors carry particularly high amounts of Her2 / neu receptors on their surface.
  • Her2 / neu receptors include, for example, lung, breast, and ovarian cancer, carcino ⁇ me, such as breast cancer, and tumors of the gastrointestinal tract.
  • the C-carbon atom is the carbonyl carbon atom of an amino acid.
  • the carbonyl groups are part of the peptide bonds between the amino acids and are located inside the peptide. This ensures that the ⁇ C carbon atom is not cleaved off the peptide, as would be possible with a side chain of one of the amino acids.
  • the C-carbon atom is the carbonyl carbon atom of the N-terminal amino acid of the peptide.
  • This embodiment is particularly preferred because the peptide can be used directly after the on ⁇ bring the 11 C-labeled amino acid.
  • 11 C-carbon has a half-life of only about 20 Minu ⁇ th, so that the radiation dose must be chosen the higher, the more time is between the synthesis of the peptide and its ⁇ ner use. If the 11 C-labeling with the N-terminal amino acid and thus in the last step of the synthesis is applied, the peptide can be used immediately after its synthesis.
  • the time between the processing of the 11 C carbon and the use of the peptide is reduced, so that the radiation loss during the preparation of the peptide is minimized. Therefore, the radiation dose that must be used in the processing of the 11 C carbon to ensure a certain radiation intensity of the product, be correspondingly lower.
  • Another object of the invention is a radiopharmaceutical comprising a peptide having an 11 C carbon atom for the localization of a tumor expressing a Her2 / neu receptor.
  • the radiopharmaceutical invention provides a host ⁇ economically and medically beneficial agent to the posi- tion of a tumor that expresses a Her2 / neu receptor to determine in vivo.
  • the peptides contained therein are distributed into the body and specifically bind to Her2 / neu receptors. As a result, they accumulate on the cells of the tumor where they are detected by the radioactive signal of the C carbon atom. In this way, the position of the tumor in the body of the patient is determined.
  • the tumor expressed in comparison to healthy tissue increased amounts of the Her2 / neu receptor, as WUR observed for various tumor types ⁇ de.
  • Carbon atom is a carbonyl carbon atom of an amino acid, preferably the carbonyl carbon atom of the N-terminal amino acid of the peptide.
  • the radiopharmaceutical is a PET biomarker.
  • 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. In contrast to the usual scintigraphic chromatography method is nenemission a more precise spatial localization of the positron by the annular configuration of the PET detectors and hence a much more precise and detailed ⁇ profiled image of the tumor possible.
  • PET also makes it possible to quantify the amount of labeled molecules in a tissue.
  • a method of localizing a tumor expressing a Her2 / neu receptor in an organism comprising the steps of a) providing a peptide, b) administering the peptide to the organism, and c) detecting the peptide in the organism Organism using positron Emission tomography (PET).
  • PET positron Emission tomography
  • the peptide used in the invention is a Her2 / neu receptor in the interior of an organism is detected and jui ⁇ Siert, so that the distribution of the Her2 / neu receptor in Kör ⁇ can be observed by a patient. In this way, for example, the size or extent of an infection or of a tumor expressing the Her2 / neu receptor can be determined.
  • the peptide used according to the invention is therefore outstandingly suitable for observing the course and success of a treatment, so-called therapy monitoring.
  • FIG. 1 shows schematically the binding between a peptide 1 and a Her2 / neu receptor 4.
  • Peptide 1 comprises 19 amino acids 2, of which the N-terminal amino acid 3 is radioactively labeled with an 11 C carbon atom.
  • the radioactive label is represented by an asterisk (*).
  • Part of the peptide 1 is attached to the Her2 / neu receptor 4, which is located on the surface of a tumor 18.
  • the 11 C-labeled peptide 1 binds specifically to the Her2 / neu receptor 4, but not to other molecules.
  • the peptide 1 can therefore be used to detect the Her2 / neu receptor 4 ⁇ .
  • the positrons released upon decay of the 11 C carbon are detected by positron emission tomography (PET).
  • PET positron emission tomography
  • the location of the positron emission corresponds to the location of peptide 1 and the bound Her2 / neu- Receptor 4.
  • Peptide 1 can therefore be used to determine the position of a tumor 18 that forms the Her2 / neu receptor 4.
  • a patient is administered a radiopharmaceutical containing the 11 C-labeled peptide 1.
  • Peptide 1 binds specifically to the Her2 / neu receptor 4 and thus accumulates on the tumor 18, whose cells form the Her2 / neu receptor 4. This accumulation is represented by PET and the distribution of the Her2 / neu receptor 4 or the localization of the tumor 18 in the body of the patient is determined. In this way, newly formed metastases carrying the Her2 / neu receptor can be identified by PET.
  • the medication of a tumor therapeutic for example, drug amount and
  • FIG. 2 shows a representation of a peptide having the sequence SEQ ID NO: 1 by means of a chemical formula.
  • the peptide of SEQ ID NO: 1 comprises 35 amino acids 2 of the following sequence: homocysteine proline aspartic acid aspartic acid tyrosine isoleucine serine arginine isoleucine lysine alanine arginine lysine glutamine glutamine asparagine asparagine Leucine-asparagine-proline-aspartic acid-leucine-alanine-alanine-glutamic acid-tryptophan-tyrosine-arginine-asparagine-arginine-methionine-glutamic acid-lysine-asparagine homocysteine.
  • the N-terminal amino acids 2 proline and homocysteine are represented by structural formula, the following amino acids 2 by their respective three-letter code.
  • the amino acid homocysteine is designated Cys H.
  • the sequence of the peptide is also given in SEQ ID NO: 1.
  • the carbonyl carbon atom of the N-terminal homocysteine is a X1 C carbon atom, represented by the number 11 above the carbonyl carbon atom.
  • Peptide 1 is prepared by conventional protein synthesis methods and the 11 C-labeled N-terminal amino acid 3 is added in the last step because the half-life of the 11 C carbon isotope is only about 20 minutes. Characterized in that the peptide synthesis is closed with the 11 C-labeled amino acid from ⁇ , Peptide 1 can be used immediately after labeling.
  • SEQ ID NO: 1 corresponds to the Her2 / neu receptor-binding 2-helix protein MUT-DS (Ren G et al., 2009).
  • the peptide of the sequence SEQ ID NO: 1 belongs to the so-called Affibodies. These are artificial peptides or proteins derived from one of the IgG-binding domains of protein A of the bacterium Staphylococcus aureus. They regularly include 3 alpha helices and are about 7 kDa in size. You do not trigger immunological reactions and are therefore geeig ⁇ net as biomolecules for preparing a radiopharmaceutical.
  • the peptide of sequence SEQ ID NO: 1 comprises only the two alpha helices actually involved in binding to the Her2 / neu receptor 4 (Ren G et al., 2009).
  • Peptide 1 binds specifically to the Her2 / neu receptor 4, which is formed in large quantities by some tumor cells, and it is used to localize ⁇ ren these tumor cells.
  • a mark by 11 C-carbon is particular ⁇ DERS suitable because it does not affect the physiological structure of the Pep ⁇ TIDS 1 and neither the tissue distribution and tolerability of the peptide 1 impaired.
  • Figure 3 shows a schematic representation (greatly simplified by Faller A, Schünke M, The Human Body, Thieme, 2008) of a circulatory system 10 of an organism and the distribution of a peptide 1 therein.
  • the circulatory system 10 comprises various schematically represented organs, such as lung 12, heart 13, liver 14, intestine 15 and kidney 16, and the main arteries 11, which connect these organs.
  • the peptide 1 is represented by triangles along the wires 11.
  • the degradation products 17 of the peptide 1 are represented by individual lines within the outline of the kidney 16 Darge ⁇ .
  • a tumor is to be ⁇ additionally shown 18, are attached to the increased Her2 / neu receptors 4 and peptides thereon. 1
  • the distribution of the peptide 1 in the circulatory system 10 comprises four phases, which are listed along the top-down view.
  • Phase I Peptide 1 is injected into the circulatory system 10 of the organism.
  • Phase II Via the circulatory system 10, the peptide 1 is transpo ted into the organs 12, 13, 14, 15, and 16 of the organism.
  • Phase III The circulating peptide 1 binds specifically to the Her2 / neu receptor 4 and accumulates on the tumor 18 because it produces the Her2 / neu receptor 4.
  • Phase IV Unbound peptide 1 is rapidly metabolised and enzymatically degraded. The organism not failed ⁇ det between own peptides and the peptide 1, because it is composed of amino acids 2, 3, which correspond to the body's own molecules. The degradation products 17 of the peptide of amino acids 1 and 2, 3 collect predominantly they are over the bladder and the ureter excreted ⁇ in the kidney 16 from where.
  • 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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Abstract

L'invention concerne l'utilisation d'un peptide (1) servant à produire un agent de détection d'une tumeur (18) qui exprime un récepteur Her2/neu (4). Ce peptide (1) se lie au récepteur Her2/neu (4) et présente un atome de carbone 1 1C. L'invention décrit également un radiopharmaceutique servant à localiser une tumeur (18) qui exprime un récepteur Her2/neu (4). Ce radiopharmaceutique comprend un peptide (1) qui se lie au récepteur Her2/neu (4) et présente un atome de carbone 1 1C.
PCT/EP2011/060447 2010-06-30 2011-06-22 Peptide marqué au 11c servant à détecter une tumeur exprimant un récepteur her2/neu WO2012000865A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE201010026061 DE102010026061A1 (de) 2010-06-30 2010-06-30 11C-markiertes Peptid zur Detektion eines Tumors, der einen Her2/neu-Rezeptor exprimiert
DE102010026061.4 2010-06-30

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WO2012000865A1 true WO2012000865A1 (fr) 2012-01-05

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Citations (7)

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WO2001083693A2 (fr) * 2000-04-28 2001-11-08 Glaxo Group Limited Composes ayant une affinite pour le recepteur 2 du facteur de croissance de l'endothelium vasculaire (vegfr-2) et utilisations associees
WO2006017619A2 (fr) * 2004-08-06 2006-02-16 The Regents Of The University Of California Peptides cycliques de liaison a un recepteur et leurs methodes d'utilisation
WO2009068625A2 (fr) 2007-11-27 2009-06-04 Ablynx N.V. Séquences d'acides aminés dirigées contre her2 et polypeptides les comprenant pour le traitement de cancers et/ou de tumeurs
WO2009080810A1 (fr) 2007-12-21 2009-07-02 Affibody Ab Nouveaux polypeptides présentant une affinité pour her2
US20100048868A1 (en) 2003-07-04 2010-02-25 Affibody Ab Polypeptides Having Binding Affinity for Her2
DE102009035645A1 (de) 2009-07-29 2011-02-03 Siemens Aktiengesellschaft Verfahren zur Herstellung eines radioaktiv markiertren Peptids
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WO2001083693A2 (fr) * 2000-04-28 2001-11-08 Glaxo Group Limited Composes ayant une affinite pour le recepteur 2 du facteur de croissance de l'endothelium vasculaire (vegfr-2) et utilisations associees
US20100048868A1 (en) 2003-07-04 2010-02-25 Affibody Ab Polypeptides Having Binding Affinity for Her2
WO2006017619A2 (fr) * 2004-08-06 2006-02-16 The Regents Of The University Of California Peptides cycliques de liaison a un recepteur et leurs methodes d'utilisation
WO2009068625A2 (fr) 2007-11-27 2009-06-04 Ablynx N.V. Séquences d'acides aminés dirigées contre her2 et polypeptides les comprenant pour le traitement de cancers et/ou de tumeurs
WO2009080810A1 (fr) 2007-12-21 2009-07-02 Affibody Ab Nouveaux polypeptides présentant une affinité pour her2
DE102009035645A1 (de) 2009-07-29 2011-02-03 Siemens Aktiengesellschaft Verfahren zur Herstellung eines radioaktiv markiertren Peptids
DE102009035648B3 (de) 2009-07-29 2011-03-17 Siemens Aktiengesellschaft Verfahren zur Herstellung eines radioaktiv markierten Carboxylats sowie die Verwendung einer Mikroelektrode zur elektrochemischen Synthese eines radioaktiv markierten Carboxylats

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FALLER A, SCHÜNKE M: "Der Körper des Menschen", 2008, THIEME-VERLAG
HARTVIG P ET AL: "Kinetics of four <11>C-labelled enkephalin peptides in the brain, pituitary and plasma of Rhesus monkeys", REGULATORY PEPTIDES, ELSEVIER SCIENCE BV, NL, vol. 16, no. 1, 1 December 1986 (1986-12-01), pages 1 - 13, XP023462538, ISSN: 0167-0115, [retrieved on 19861201], DOI: 10.1016/0167-0115(86)90190-4 *
HENRIKSEN G ET AL: "Proof of principle for the use of 11C-labelled peptides in tumour diagnosis with PET", EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, SPRINGER VERLAG, HEIDELBERG, DE, vol. 31, no. 12, 10 August 2004 (2004-08-10), pages 1653 - 1657, XP002383248, ISSN: 1619-7070, DOI: 10.1007/S00259-004-1582-1 *
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WIKMAN M, STEFFEN AC, GUNNERIUSSON E, TOLMACHEV V, ADAMS GP, CARLSSON J, STAHL S: "Selection and characterization of HER2/neu-binding affibody ligands", PROTEIN ENG DES SEL., vol. 17, no. 5, May 2004 (2004-05-01), pages 455 - 62, XP002982293, DOI: doi:10.1093/protein/gzh053

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