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WO2012002388A1 - Agent destiné à l'administration d'un médicament à un ganglion sentinel - Google Patents

Agent destiné à l'administration d'un médicament à un ganglion sentinel Download PDF

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Publication number
WO2012002388A1
WO2012002388A1 PCT/JP2011/064808 JP2011064808W WO2012002388A1 WO 2012002388 A1 WO2012002388 A1 WO 2012002388A1 JP 2011064808 W JP2011064808 W JP 2011064808W WO 2012002388 A1 WO2012002388 A1 WO 2012002388A1
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Prior art keywords
icam
drug
agent
cancer
antibody
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English (en)
Japanese (ja)
Inventor
俊夫 大橋
佳子 河合
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Shinshu University NUC
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Shinshu University NUC
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Priority to JP2012522643A priority Critical patent/JPWO2012002388A1/ja
Publication of WO2012002388A1 publication Critical patent/WO2012002388A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2821—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against ICAM molecules, e.g. CD50, CD54, CD102
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
    • A61K49/0043—Fluorescein, used in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0058—Antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a drug transporter for selectively transporting a drug for the diagnosis of the presence or absence of microcarcinoma metastasis in a lymph node that first receives lymphatic flow from a primary cancer lesion, particularly a sentinel lymph node, and treatment therefor. Is.
  • Cancer cell metastasis from the primary cancer site to various organs and tissues throughout the body is mainly caused by lymphatics.
  • Treatment methods for such metastatic cancer diseases include surgical treatment for removing the primary tumor, oral administration of anticancer agents and chemotherapy by intravenous injection.
  • lymph node dissection involves dissection of lymph nodes that may have metastasized together with the primary tumor and surrounding tissues.
  • lymph node dissection has a complicated surgical procedure and a great physical burden on the patient.
  • lymph node metastasis was performed in order to examine postoperatively whether the lymphatic system that had metastasized could be completely dissected, and whether there was a possibility of re-metastasis of cancer cells to the lymphatic system.
  • Laboratory tests on the extensive lymphatic system as indicators should be performed.
  • the cancer primary lesion is determined prior to the surgery.
  • Sentinel Lymph Node SSN
  • Mirin Lymph Node the first local lymph node to receive lymph flow by injecting dyes and radioactive isotopes from the primary cancer through the imported lymphatic vessels, and biopsy Therefore, pathological clinical tests for identifying the presence or absence of cancer cell metastasis have been conducted.
  • the same examination can be performed after surgery to appropriately determine the presence or absence of prognostic metastasis.
  • cancer cells are more likely to metastasize or metastasize, especially sentinel lymph nodes, and the drug is selectively delivered to the primary cancerous lesion, surrounding tissues, and lymphatic system. Therefore, there is a demand for a drug transport agent that can be safely treated while reducing the burden on the patient.
  • Patent Document 1 the present inventors established a human lymphatic cell-derived endothelial cell line collected by detachment by perfusing a collagenase solution into the lumen of the extracted human lymphatic vessel. ing.
  • the present inventors have found that the primary tumor affects the microenvironment of the sentinel lymph node at a pre-metastasis stage, and a specific intercellular adhesion molecule such as ICAM-1 (inter- cellular adhesion molecule-1) is expressed due to various causative substances such as ATP (adenosine triphosphate) and CCL2 (CC Chemokine Ligand 2) derived from cancer cells, and in the sentinel lymph node, It was found that it was involved in the adhesion between cancer cells and the lymphatic endothelial cells and induced an environment that facilitates micrometastasis.
  • ICAM-1 inter- cellular adhesion molecule-1
  • CCL2 CC Chemokine Ligand 2
  • the present invention has been made to solve the above-mentioned problems, and specifically detects lymph nodes, particularly sentinel lymph nodes, in which cancer cells are easy to metastasize or micro cancer metastasis is already recognized in vivo.
  • the drug to be treated can be selectively delivered, and the drug used for treatment can be selectively and efficiently delivered to the primary cancer lesion and its surrounding tissues. It is an object to provide a drug transporter that can alleviate cancer and reliably treat cancer diseases.
  • the drug transporter according to claim 1, wherein the anti-ICAM-1 antibody that binds to ICAM-1 expressed on lymph node endothelial cells is fluorescently labeled. It is characterized by being contained as a drug transporting active ingredient while being chemically modified with at least one of a drug, a radioisotope-containing labeling agent, a contrast agent, and an anticancer agent.
  • the drug transporter according to claim 2 is the drug transporter according to claim 1, wherein the drug is chemically modified directly with a binding group or via a binding group of a spacer molecule, and the It is characterized by binding to an ICAM-1 antibody.
  • a drug transporter according to claim 3 is the drug transporter according to claim 1, wherein the drug is the fluorescent labeling agent selected from a fluorescein derivative, a rhodamine derivative, a phycoerthrin derivative, and a sulfonated coumarin derivative. It is characterized by that.
  • the drug transport agent according to claim 4 is the drug transport agent according to claim 1, wherein the drug transport active ingredient is free or encapsulated in colloidal particles.
  • FIG. 2 is a fluorescent image photograph showing the degree of expression of ICAM-1 when cultured lymphatic endothelial cells are stimulated with a culture supernatant of a breast cancer cell line, ATP and CCL2. It is the bright field image photograph and fluorescence image photograph which image
  • phycoerthrin which is a chromoprotein that exhibits an absorption wavelength on the longer wavelength side, or a derivative thereof, and is a dye series such as Alexa ⁇ Fluor (Invitrogen, registered trademark) 305 or 488, which is a sulfonated coumarin derivative. May be.
  • the anti-ICAM-1 antibody is preferably a monoclonal antibody, but may be a polyclonal antibody.
  • the animal derived from this anti-ICAM-1 antibody is exemplified by a mouse, but it may be a human.
  • Such a fluorescein fluorescently labeled human anti-ICAM-1 antibody is derived from a human when administered as a drug transport agent, and thus is difficult to recognize as a foreign antigen in the patient's body. It reaches to the part of the period.
  • an antibody and a fluorescent labeling agent are directly bound by a thiocarbamide binding group derived from an isothiocyan group in the fluorescent labeling agent. If it is a thing, a coupling group will not be specifically limited.
  • the antibody and the fluorescent labeling agent may be bound via a spacer molecule.
  • the spacer molecule may be a secondary antibody that is a protein or a biotin-avidin complex, and is an ester bond such as a polycarboxylic acid such as a low molecular weight maleic acid derivative or an agonitic acid derivative, or polyerylene glycol (PEG). Or a polyfunctional compound via an ether bond.
  • the fluorescence-labeled anti-ICAM-1 antibody immunologically binds to ICAM-1 of a cell and then emits fluorescence when irradiated with light emitted from a laser beam, a high-pressure mercury lamp or a halogen lamp. By detecting with, it is confirmed visually or by image processing.
  • radioisotope-containing labeling agents examples include fluorescent labeling agents, contrast agents, and anticancer agents.
  • a radioisotope-containing labeled anti-ICAM-1 antibody may be used in place of the fluorescently labeled anti-ICAM-1 antibody as described above.
  • Such a radioisotope-containing labeled anti-ICAM-1 antibody includes, for example, stable radioactive iodine 125 I and 131 I, and N-hydroxysuccinimide ester of 3- (4-hydroxyphenyl) propionic acid which is a Bolton-Hunter reagent.
  • an unlabeled anti-ICAM-1 antibody Chloramine T, radioactive sodium iodine and anti-ICAM-1 antibody may be mixed.
  • a contrast agent such as a non-radioactive iodine agent, electromagnetic wave reflection or absorption agent may be prepared by chemical modification as described above.
  • an anticancer agent such as methotrexate or adriamycin may be bound in the same manner as described above.
  • the dosage form of the drug transport agent is not particularly limited, but the drug transport agent may be composed of only the drug transport active ingredient while the anti-ICAM-1 antibody chemically modified with the drug is released. It may be included or contained.
  • the colloidal particles are preferably liposomes formed of phosphatidylserines, specifically phosphatidylserine salts, more specifically hydrogenated egg yolk phosphatidylserine sodium as a main component.
  • the colloidal particles may be liposomes formed with phospholipids such as distearoyl phosphatidylcholine (DSPC), distearoyl phosphatidylethanolamine (DSPE).
  • the colloidal particles may be liposomes formed of phospholipids such as lecithin, biodegradable resin micelle particles, or synthetic resin micelle particles. Of these, liposomes are particularly preferred.
  • the dose of this drug transporter is preferably 10-30 ⁇ g / kg in terms of anti-ICAM-1 antibody.
  • a drug transporter comprising a drug transporter active ingredient comprising an anti-human ICAM-1 antibody fluorescently labeled with a fluorescein derivative
  • a method of using it for imaging and diagnosing a sentinel lymph node of a cancer patient will be described .
  • This drug transporter is administered to an extravascular tissue of a cancer patient, for example, a breast cancer patient, for example, submucosa or subcutaneous tissue in the vicinity of the primary tumor located upstream of the lymphatic system including the sentinel lymph node to be visualized.
  • This drug transport agent flows into the lymphatic import lymphatic vessels together with the lymph fluid derived from the plasma component that has exuded into the interstitial space, slowly flows through the lymphatic vessels, and finally reaches the sentinel lymph node.
  • an intercellular adhesion molecule ICAM-1 is expressed by causing a microenvironmental change caused by cancer cells at the primary tumor.
  • EGM-2 endothelial growth medium
  • FBS fetal bovine serum
  • a human collecting lymphatic vessel-derived endothelial cell line was isolated and cultured as follows.
  • a breast cancer patient who also obtained consent received donation of human collecting lymphatic vessels, which are imported lymphatic vessels of human axillary lymph nodes, with the surrounding tissues removed at the time of surgery attached.
  • tissues such as fat and capillaries around the lymphatic vessels were exfoliated under a stereomicroscope.
  • a thin polyethylene tube was inserted into the lumen of the human collecting lymph vessel and left in place for perfusion, washing and cell collection. The lumen was washed by perfusion with phosphate buffered saline (PBS solution).
  • PBS solution phosphate buffered saline
  • This lumen was filled with 0.05% collagenase II solution (manufactured by Worthington, USA; product number S2B5456). It was allowed to stand in a 37 ° C. incubator for a period in which endothelial cell detachment was observed, mainly for 10 minutes.
  • As a medium and medium supplement 500 ml of growth medium bullet kit EGM-2 for vascular endothelial cells (Sanko Junyaku Co., Ltd .; product number CC-3162) and fetal bovine serum (FBS) (manufactured by Japan Bioserum; product number) S1560) 40 ml was used.
  • Mycoplasma removal was carried out by 0.5 ⁇ g / ml alone or in combination. Even after mycoplasma was reversed, the mycoplasma infection status was confirmed with the above-mentioned infection measurement kit in a timely manner (every 2 passages), and a mycoplasma negative cell line was established.
  • a cell suspension is prepared using 2 and cultured in the same manner as in the above-mentioned endothelial cell line culture conditions.
  • VEGF-R3 vascular endothelial growth factor receptor 3
  • the human collecting lymphatic vessel-derived endothelial cell line transferred to the culture system was seeded on a slide glass. When the culture was continued and became confluent, it was fixed with 10% formalin. After blocking with a PBS solution containing 0.1% bovine serum albumin (BSA), VEGF-R3 (manufactured by Santa Cruz, USA; product number sc-637), which is a specific marker of lymphatic endothelial cells, is used as a primary antibody. : 100 diluted with 0.1% BSA-added PBS solution, and allowed to stand at 4 ° C. overnight.
  • BSA bovine serum albumin
  • LYVE-1 lymphatic vessel endothelial hyaluronan receptor-1
  • LYVE-1 lymphatic vessel endothelial hyaluronan receptor-1
  • TNF- ⁇ tumor necrosis factor- ⁇
  • IL-1 ⁇ interleukin-1 ⁇
  • the negative control without a stimulating factor showed an unclear green fluorescent color and expressed less F-actin, whereas it was stimulated with TNF- ⁇ or IL-1 ⁇ .
  • the product showed a clear green fluorescent color, confirming an increase in the expression of F-actin.
  • This human lymphatic endothelial cell line was received by the National Institute of Advanced Industrial Science and Technology Patent Biological Depositary Center (1-1-1 East Tsukuba City, Ibaraki Prefecture) on January 18, 2006 and received the domestic accession number FERM P -20768, which was applied to the center for international deposit on January 16, 2009, and was given the accession number FERM BP-11089.
  • Test 1 Expression of ICAM-1 in cultured lymphatic endothelial cells
  • MDA-MB-231 which is a human breast cancer cell line
  • FBS Dulbecco's modified Eagle medium
  • the cancer cells were cultured at 37 ° C. under standard oxygen conditions of 21% oxygen, 5% carbon dioxide, and 74% nitrogen gas.
  • lymphatic endothelial cells were cultured at 37 ° C. under atmospheric conditions of oxygen 5%, carbon dioxide gas 5%, and nitrogen gas 90%.
  • ATP concentration of the supernatant was 1.0 ⁇ 10 -7 M by luciferin-luciferase reaction measured.
  • stimulation was performed with a 10 ⁇ 7 M aqueous solution of ATP and 10 ng / mL of CCL2, and those treated in the same manner as the supernatant were prepared. What was not stimulated was made as a control.
  • Indirect immunohistochemical observation was performed on cultured lymphatic endothelial cells seeded on type I collagen-coated slide glass, and the cells were incubated with phosphate buffered saline (PBS) containing 3.3% formalin for 20 minutes. And fixed at room temperature. The cells were washed 3 times with PBS and then cultured overnight at 4 ° C. with primary polyclonal human antiserum of ICAM-1 / CD54 (dilution 10 ⁇ g / mL, manufactured by R & D® Systems, USA).
  • PBS phosphate buffered saline
  • Cancer cells were infiltrated with 0.1% Triton X before primary staining. After washing 3 times with PBS, the cells were cultured for 1 hour at room temperature using Alexa Fluor 488 anti-mouse immunoglobulin G (manufactured by Invitrogen, USA) diluted 1: 100. The cell nuclei of the cultured cells are stained with a counterstain, and ProLong Gold non-bleaching reagent containing 4 ′, 6-diamidine-2-phenylindole (DAPI) (Molecular Probes, USA) is added, followed by fluorescence microscopy (Leica, Switzerland). Observed) and photographed.
  • DAPI ProLong Gold non-bleaching reagent containing 4 ′, 6-diamidine-2-phenylindole
  • Test 2 Adhesion test between cultured lymphatic endothelial cells and breast cancer cells
  • Conditions of 5% oxygen, 5% carbon dioxide, and 90% nitrogen gas at 37 ° C. until a human lymphatic endothelial cell is formed into a monolayer and becomes confluent on a 35 mm diameter culture dish coated with type I collagen Under culture.
  • the lymphatic endothelial cells were stored in EBM-2 serum starvation medium containing 3% FBS.
  • Culture dish (i) Serum starvation medium only (negative control) (ii) Addition of 10 -7 M ATP (positive control) (iii) of 10 -7 M of ATP + 10 -6 M suramin (iv) 10 ⁇ 7 M ATP + anti-ICAM-1 antibody (v) MDA-MB-231 culture supernatant (positive control) (vi) MDA-MB-231 culture supernatant + 10 -6 M suramin (vii) The culture supernatant of MDA-MB-231 + anti-ICAM-1 antibody was used for stimulation for 48 hours, respectively.
  • 10 ⁇ 6 M suramin acts as an inhibitor of ATP receptor, and was added at the same time when stimulation with 10 ⁇ 7 M ATP or MDA-MB-231 cell culture supernatant for 48 hours.
  • the culture dish was stimulated with 10 ⁇ 7 M ATP or MDA-MB-231 cell culture supernatant for 48 hours and then treated with anti-human ICAM-1 antibody (manufactured by R & D Systems, USA) for 30 minutes.
  • Example 1 Example of Monoclonal Anti-rat ICAM-1-Fluorescein (R & D Systems, product number FAB5831F) used as a drug transport agent containing FITC-labeled anti-rat ICAM-1 antibody as a drug transport active ingredient and used to depict sentinel lymph nodes It is shown below.
  • FIG. 2 shows “ATP not administered with 10 ⁇ 6 M”.
  • the drug transporter of the present invention is used for identifying a sentinel lymph node to be dissected and conducting a pathological examination before or during a surgical cancer treatment.
  • pathological examination to check whether the cancer has recurred and lymphatic metastasis has occurred after the surgery.
  • medical examinations such as a medical checkup and preventive medicine.

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Abstract

L'invention concerne un agent destiné à l'administration d'un médicament, ledit agent pouvant, dans un organisme vivant, administrer sélectivement un agent médicinal apte à détecter ou traiter spécifiquement un ganglion lymphatique, en particulier un ganglion sentinel, dans lequel une cellule cancéreuse est susceptible de devenir métastatique ou dans lequel le développement d'une métastase cancéreuse minimale a été observée; ledit agent pouvant sélectivement et avec grande efficacité administrer un agent médicinal apte à être utilisé aux fins de traitement dans un site primaire du cancer ou dans un tissu entourant le site primaire; ledit agent étant inoffensif et moins invasif, étant moins lourd pour les patients, et étant apte à traiter une maladie cancéreuse avec une grande fiabilité. L'agent destiné à l'administration d'un médicament contient, en tant qu'ingrédient actif en termes d'administration de médicament, un anticorps anti-ICAM-1 qui peut se lier à ICAM-1 exprimé sur une cellule endothéliale d'un ganglion lymphatique et est chimiquement modifié par au moins une substance chimique sélectionnée parmi un agent de marquage fluorescent, un agent de marquage contenant un isotope radioactif, un colorant de contraste et un agent anti-cancer.
PCT/JP2011/064808 2010-07-01 2011-06-28 Agent destiné à l'administration d'un médicament à un ganglion sentinel Ceased WO2012002388A1 (fr)

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JP2012522643A JPWO2012002388A1 (ja) 2010-07-01 2011-06-28 センチネルリンパ節への薬物輸送剤

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114929263A (zh) * 2019-08-23 2022-08-19 儿童医学中心公司 胞间黏附分子1（icam1）抗体药物缀合物及其用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009116322A1 (fr) * 2008-02-29 2009-09-24 国立大学法人信州大学 Kit pour détecter des cellules cancéreuses se métastasant dans un ganglion lymphatique sentinelle

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009116322A1 (fr) * 2008-02-29 2009-09-24 国立大学法人信州大学 Kit pour détecter des cellules cancéreuses se métastasant dans un ganglion lymphatique sentinelle

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114929263A (zh) * 2019-08-23 2022-08-19 儿童医学中心公司 胞间黏附分子1（icam1）抗体药物缀合物及其用途
JP2022546387A (ja) * 2019-08-23 2022-11-04 ザ チルドレンズ メディカル センター コーポレーション 細胞間接着分子１（ｉｃａｍ１）抗体薬物抱合体およびそれらの使用

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