WO2017026276A1 - Composition pharmaceutique contenant un conjugué de protéine et de composé contenant du bore - Google Patents

Composition pharmaceutique contenant un conjugué de protéine et de composé contenant du bore Download PDF

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Publication number
WO2017026276A1
WO2017026276A1 PCT/JP2016/071899 JP2016071899W WO2017026276A1 WO 2017026276 A1 WO2017026276 A1 WO 2017026276A1 JP 2016071899 W JP2016071899 W JP 2016071899W WO 2017026276 A1 WO2017026276 A1 WO 2017026276A1
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WIPO (PCT)
Prior art keywords
compound
boron
mid
protein
pharmaceutical composition
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PCT/JP2016/071899
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English (en)
Japanese (ja)
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中村　浩之
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国立大学法人東京工業大学
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Priority to JP2017534171A priority Critical patent/JP6788278B2/ja
Publication of WO2017026276A1 publication Critical patent/WO2017026276A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein

Definitions

  • Boron neutron capture therapy and (Boron Neutron Capture Therapy BNCT) is a human body is captured by the boron agents harmless low energy thermal neutrons in, by reaction with thermal neutron and 10 B, and lithium microenvironment in one cell It is a new cancer treatment that destroys cancer cells by generating alpha rays.
  • Non-patent Document 1 The area around the tumor tissue that is immature in blood vessel formation has a characteristic that particles such as liposomes are likely to accumulate. Based on this characteristic, a delivery system of boron to cancer cells using liposomes has been developed. For example, the present inventors have succeeded in developing a system capable of delivering boron at a very high concentration by introducing a boron compound into a lipid bilayer membrane of a liposome (Non-patent Document 1). In addition, boron has been highly integrated by introducing a boron compound into a liposome membrane into which a boron compound has been introduced (Non-patent Document 2).
  • X in the formula (I) may be any group containing 10 B, and may be a group derived from a compound having one boron atom in the molecule such as BPA. Derived groups are preferred.
  • the boron cluster may be any polyhedral structure that can be used for boron neutron capture therapy, for example, clothododecaborate ([B 12 H 12 ] 2- ), ionic crosocarborane ([CB 11 H 12 ] - ), fat-soluble crosocarborane ([C 2 B 10 H 12 ]), nidocarborane ([C 2 B 9 H 11 ] - ), bisdicarbollide metal complex ([(C 2 B 9 H 11 ) 2 M ], GB10 ([B 10 H 12 ] 2 ⁇ ) and the like.
  • the compound represented by the formula (I) can be synthesized according to the method described in the Examples or according to a method in which those methods are appropriately modified or modified with reference to the description.
  • a linker can be bound to a compound that can derive a group containing 10 B (such as clothododecaborate or BSH), and a compound that can induce a group that binds to a lysine residue (such as maleimide or TCDI) can be bound to this linker.
  • a linker can be bound to a compound that can derive a group containing 10 B (such as clothododecaborate or BSH), and a compound that can induce a group that binds to a lysine residue (such as maleimide or TCDI) can be bound to this linker.
  • a group containing 10 B such as clothododecaborate or BSH
  • a compound that can induce a group that binds to a lysine residue such as maleimide or
  • Example 1 Synthesis of MID (1) Synthesis of Compound 3 It is a compound known in the literature (Igor B. Sivaev, Nadezhda Yu. Kulikova, Evgeniya A. Nizhnik, Maxim V. Vichuzhanin, Zoya A. Starikova, Andrei A. Semioshkin, and Vladimir I. Bregadze, J. Organomet. Chem. 2008 , 693, 519-525) Compound 4 (1.3 g, 2.0 mmol) as a starting material, 1 ml NaBF 4 (1.1 g, 10.0 mmol) and 4 M HCl, 70 ml 1,4-dioxane, and temperature The mixture was heated to reflux at 100 ° C.
  • Example 2 Biodistribution of MID-BSA conjugate MID and BSA were mixed at a molar ratio of 10: 1 in PBS (pH 7.4) and reacted at 23 ° C for 12 hours to obtain a MID-BSA conjugate. A gate was generated. This MID-BSA conjugate was injected into the tail vein of BALB / c mice inoculated with CT26 (mouse colon cancer cell line). The injection amount of MID-BSA conjugate was adjusted to 3 to 30 mg B / kg. The boron concentration in blood, tumor tissue, liver, kidney and spleen after injection was measured using ICP-AES.
  • Tf has been found not to contain free -SH, and normally compounds containing maleimide do not bind to Tf.
  • FIG. 8 it was found that MID has higher binding ability than BCS for NSA at pH 7.4 (lanes 2 and NC3) than NCS-dodecaborate sodium salt (compound 11).
  • MID also binds to Tf that does not contain free -SH in the same manner as NCS-dodecaborate-sodium salt (compound 11) (lanes 5 and 6).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention vise à établir un moyen pour distribuer sélectivement une grande quantité de bore à un tissu tumoral. Pour cela, l'invention propose une composition pharmaceutique contenant un conjugué d'un composé de formule (I) : X-L-Y (dans laquelle X représente un groupe comprenant 10B, L représente un groupe de liaison et Y représente un groupe lié à un résidu de lysine) et d'une protéine à accumulation tumorale comportant un résidu de lysine. Le rapport molaire (nombre de moles du composé/nombre de moles de la protéine) du composé et de la protéine contenus dans la composition est supérieur à dix.
PCT/JP2016/071899 2015-08-07 2016-07-26 Composition pharmaceutique contenant un conjugué de protéine et de composé contenant du bore WO2017026276A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2017534171A JP6788278B2 (ja) 2015-08-07 2016-07-26 ホウ素含有化合物とタンパク質とのコンジュゲートを含む医薬組成物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2015-156726 2015-08-07
JP2015156726 2015-08-07

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WO2017026276A1 true WO2017026276A1 (fr) 2017-02-16

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017164334A1 (fr) * 2016-03-23 2017-09-28 公益財団法人 川崎市産業振興財団 Composé peptidique lié à un agrégat de bore
JP2019038778A (ja) * 2017-08-25 2019-03-14 国立大学法人東京工業大学 ホウ素含有葉酸誘導体
WO2019160129A1 (fr) * 2018-02-15 2019-08-22 国立大学法人 岡山大学 Évaluation de tissu de lésion cancéreuse pour optimiser l'effet d'une thérapie par capture de neutrons de bore
WO2019244954A1 (fr) * 2018-06-20 2019-12-26 国立大学法人弘前大学 Médicament d'accumulation de bore 10 pour une thérapie par capture de neutrons par le bore pour cibler sélectivement ou localement des tissus tumoraux en temps court
CN112080458A (zh) * 2020-09-14 2020-12-15 中国石油大学(华东) 一种用于蛋白质胞内递送的方法
WO2022092068A1 (fr) * 2020-10-30 2022-05-05 京都府公立大学法人 Composé carborane, sel de celui-ci ou solvate de celui-ci
WO2022191262A1 (fr) * 2021-03-12 2022-09-15 国立大学法人東京工業大学 Nouveau médicament au bore

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001500133A (ja) * 1996-09-11 2001-01-09 フェリックス クラッツ トランスフェリン、アルブミン及びポリエチレングリコールの抗腫瘍性の複合体
JP2015503585A (ja) * 2012-01-03 2015-02-02 インビクタス オンコロジー プライベート リミテッド リガンド−標的指向分子およびその方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001500133A (ja) * 1996-09-11 2001-01-09 フェリックス クラッツ トランスフェリン、アルブミン及びポリエチレングリコールの抗腫瘍性の複合体
JP2015503585A (ja) * 2012-01-03 2015-02-02 インビクタス オンコロジー プライベート リミテッド リガンド−標的指向分子およびその方法

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MIYAJIMA, Y. ET AL.: "Transferrin-loaded nido-carborane liposomes: tumor-targeting boron delivery system for neutron capture therapy", BIOCONJUG. CHEM., vol. 17, no. 5, 2006, pages 1314 - 1320, XP055363719, ISSN: 1043-1802 *
MIZUSAWA, E.A. ET AL.: "Synthesis and antibody-labeling studies with the p-isothiocyanatobenzene derivatives of 1,2-dicarba-closo-dodecarborane(12) and the dodecahydro-7,8-dicarbanido-undecaborate(-1) ion for neutron-capture therapy of human cancer. Crystal and molecular structure of Cs+[nido-7-(p-C6H4NCS)-9-I-7,8-C2B9H11]", INORG. CHEM., vol. 24, no. 12, 1985, pages 1911 - 1916, ISSN: 0020-1669 *
WILBUR, D.S. ET AL.: "Streptavidin in antibody pretargeting. 5. chemical modification of recombinant streptavidin for labeling with the alpha-particle-emitting radionuclides 213Bi and 211At", BIOCONJUG. CHEM., vol. 19, no. 1, 2008, pages 158 - 170, XP055363724, ISSN: 1043-1802 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017164334A1 (fr) * 2016-03-23 2017-09-28 公益財団法人 川崎市産業振興財団 Composé peptidique lié à un agrégat de bore
JP7154528B2 (ja) 2017-08-25 2022-10-18 国立大学法人東京工業大学 ホウ素含有葉酸誘導体
JP2019038778A (ja) * 2017-08-25 2019-03-14 国立大学法人東京工業大学 ホウ素含有葉酸誘導体
WO2019160129A1 (fr) * 2018-02-15 2019-08-22 国立大学法人 岡山大学 Évaluation de tissu de lésion cancéreuse pour optimiser l'effet d'une thérapie par capture de neutrons de bore
CN111971563A (zh) * 2018-02-15 2020-11-20 立美基股份有限公司 用于优化硼中子俘获疗法的效应的癌病变组织评估
CN111971563B (zh) * 2018-02-15 2023-09-08 立美基股份有限公司 用于优化硼中子俘获疗法的效应的癌病变组织评估
JPWO2019160129A1 (ja) * 2018-02-15 2021-03-04 国立大学法人 岡山大学 ホウ素中性子捕捉療法の効果を最適化するがん病巣組織評価
JP7221539B2 (ja) 2018-02-15 2023-02-14 国立大学法人 岡山大学 ホウ素中性子捕捉療法の効果を最適化するがん病巣組織評価
WO2019244954A1 (fr) * 2018-06-20 2019-12-26 国立大学法人弘前大学 Médicament d'accumulation de bore 10 pour une thérapie par capture de neutrons par le bore pour cibler sélectivement ou localement des tissus tumoraux en temps court
JPWO2019244954A1 (ja) * 2018-06-20 2021-07-01 国立大学法人弘前大学 ホウ素中性子捕捉療法用の腫瘍組織を短時間で選択的ないし局所的に標的化できる集積性ボロン１０薬剤
JP7440914B2 (ja) 2018-06-20 2024-02-29 国立大学法人弘前大学 ホウ素中性子捕捉療法用の腫瘍組織を短時間で選択的ないし局所的に標的化できる集積性ボロン１０薬剤
CN112080458A (zh) * 2020-09-14 2020-12-15 中国石油大学(华东) 一种用于蛋白质胞内递送的方法
WO2022092068A1 (fr) * 2020-10-30 2022-05-05 京都府公立大学法人 Composé carborane, sel de celui-ci ou solvate de celui-ci
WO2022191262A1 (fr) * 2021-03-12 2022-09-15 国立大学法人東京工業大学 Nouveau médicament au bore

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JPWO2017026276A1 (ja) 2018-05-24

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