JP6789961B2 - インテグリン標的タンパク質およびその使用方法 - Google Patents
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- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229960002324 trifluoperazine Drugs 0.000 description 1
- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 description 1
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- ZSCDBOWYZJWBIY-UHFFFAOYSA-N trimipramine Chemical compound C1CC2=CC=CC=C2N(CC(CN(C)C)C)C2=CC=CC=C21 ZSCDBOWYZJWBIY-UHFFFAOYSA-N 0.000 description 1
- FYZXEMANQYHCFX-UHFFFAOYSA-K tripotassium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [K+].[K+].[K+].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O FYZXEMANQYHCFX-UHFFFAOYSA-K 0.000 description 1
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Classifications
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70546—Integrin superfamily
- C07K14/70557—Integrin beta3-subunit-containing molecules, e.g. CD41, CD51, CD61
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- 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
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70546—Integrin superfamily
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- 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
- A61K47/56—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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Description
本願は、2015年3月6日に出願された、米国仮特許出願第62/129,499号に対する利益を主張し、その全体が、参照により本明細書の一部をなすものとする。
本発明は、米国国立衛生研究所によって与えられたCA175122に基づく政府の支援により作製された。本政府は、本発明において一定の権利を有する。
本願は、線維症に関連する医学的症状の治療に有効であり得る化合物またはタンパク質に関する。本開示は、概して、αvβ3インテグリンに特異的に結合するポリペプチドに関する。本開示はさらに、血管形成、細胞増殖、および線維症を減らすための、および、がん、門脈圧亢進症、ならびに線維症関連の疾患および症状を治療するためのポリペプチドの使用方法に関する。
「血管形成」は、組織灌流に有効な新規の血管系の形成として定義される。これは、既存の血管からの内皮細胞の発芽による新規血管の形成、または組織の血液灌流を改善するために大きさ、熟成方向、または流動特性を変更するための既存の血管の再構築を含む。
1 KEITNALETWGALGQDINLDIPSFQMSDDIDDIKWEKTSDKKKIAQFRKEKETFKEKDTYKLFKNGTLKIKHLKTDDQDIYKVSIYDTKGKNVLEKIFDLKIQER 106(配列番号1)
と少なくとも約75%類似するアミノ酸配列を有するD1−CD2のバリアントに関する。本開示はさらに、血管形成、細胞増殖、がん、ならびに線維症に関連する疾患および症状の治療におけるポリペプチドの使用方法に関する。本開示はまた、α2ヘリックス、B−Cループおよびα2−α3ループの領域中のβAドメインにおいてαvβ3インテグリンに特異的に結合する単離されたポリペプチドを含む。かかるポリペプチドの例は、ProAgioである。ProAgioの例示的な配列には、
KEITNALETWGALGQDINLDIPSFQMSDDIDDIKWEKTSDKKKIAQFRKEKETFKEKDTYKLFKNGTLKIKHLKTDDQDIYKVSIYDTKGKNVNDVCNFASRQER(配列番号2)
および
KEITNALETWGALGQDINLDIPSFQMSDDIDDIKWEKTSDKKKIAQFRKEKETFKEKD TYKLFKNGTLKIKHLKTDDQDIYKVSIYDTKGKNVLEKYDYLKIQER(配列番号3)
が含まれる。
Claims (25)
- 対象の傷害または損傷組織における細胞外マトリクス内の線維性物質の過度の蓄積を防ぐか、または減らすための医薬組成物であって、前記医薬組成物が、αvβ3インテグリンに特異的に結合するポリペプチドを含み、前記ポリペプチドが、野生型細胞接着性タンパク質のドメイン1(D1−CD2)のバリアントを含み、前記バリアントが、配列番号2または配列番号3の配列からなる、医薬組成物。
- 前記ポリペプチドが、約1μM未満の解離定数を有する、請求項1に記載の医薬組成物。
- 前記対象が、肝線維症、膵線維症、または乳腺線維症を有する、請求項1に記載の医薬組成物。
- 前記バリアントが、αvβ3インテグリンとの少なくとも1つの分子間相互作用を有する、請求項1に記載の医薬組成物。
- 前記バリアントが、βA溝においてαvβ3インテグリンに結合する、請求項1に記載の医薬組成物。
- 前記バリアントが、TEMKQERにおいてαvインテグリンに架橋される、請求項1に記載の医薬組成物。
- 前記バリアントが、FNEEVKKQにおいてβ3インテグリンに架橋される、請求項1に記載の医薬組成物。
- 前記バリアントが、FNEEVKKQにおいてβ3インテグリンに架橋される、請求項1に記載の医薬組成物。
- 前記バリアントが、PEG化されている、請求項1に記載の医薬組成物。
- 前記バリアントが、ポリエチレングリコールによりPEG化されている、請求項1に記載の医薬組成物。
- 前記ポリエチレングリコールが、PEG−20kDaである、請求項1に記載の医薬組成物。
- 対象の組織内でアポトーシスを誘導するための医薬組成物であって、前記医薬組成物が、α2ヘリックス、B−Cループ、およびα2−α3ループの領域中のβAドメインにおいてαvβ3インテグリンに特異的に結合する治療的に有効な量のポリペプチドを含み、前記ポリペプチドが、野生型細胞接着性タンパク質のドメイン1(D1−CD2)のバリアントを含み、前記バリアントが、配列番号2または配列番号3の配列からなり、それによって前記対象の前記組織における細胞外マトリクス内の線維性物質の過度の蓄積を防ぐか、または減らす、医薬組成物。
- 肝臓の門脈圧亢進症を防ぐか、または減らすための医薬組成物であって、前記医薬組成物が、α2ヘリックス、B−Cループ、およびα2−α3ループの領域中のβAドメインにおいてαvβ3インテグリンに特異的に結合する治療的に有効な量のポリペプチドを含み、前記ポリペプチドが、野生型細胞接着性タンパク質のドメイン1(D1−CD2)のバリアントを含み、前記バリアントが、配列番号2または配列番号3の配列からなり、それによって対象の組織における細胞外マトリクス内の線維性物質の過度の蓄積を防ぐ、または減らす、医薬組成物。
- 前記対象が、肝線維症を有する、請求項13に記載の医薬組成物。
- 前記対象が、膵線維症を有する、請求項13に記載の医薬組成物。
- 前記対象が、乳腺線維症を有する、請求項13に記載の医薬組成物。
- 対象の組織における細胞外マトリクス内に線維性物質の過度の蓄積を有する疾患を治療するための医薬組成物であって、前記医薬組成物が、α2ヘリックス、B−Cループ、およびα2−α3ループの領域中のβAドメインにおいてαvβ3インテグリンに特異的に結合する治療的に有効な量のポリペプチドを含み、前記ポリペプチドが、野生型細胞接着性タンパク質のドメイン1(D1−CD2)のバリアントを含み、前記バリアントが、配列番号2または配列番号3の配列からなり、それによって前記対象の前記組織における細胞外マトリクス内の線維性物質の過度の蓄積を防ぐか、または減らす、医薬組成物。
- 前記疾患が、肝線維症または膵線維症である、請求項17に記載の医薬組成物。
- 対象内の腫瘍を予防し、かつ治療するための医薬組成物であって、前記医薬組成物が、α2ヘリックス、B−Cループ、およびα2−α3ループの領域中のβAドメインにおいてαvβ3インテグリンに特異的に結合する治療的に有効な量のポリペプチドを含み、前記ポリペプチドが、野生型細胞接着性タンパク質のドメイン1(D1−CD2)のバリアントを含み、前記バリアントが、配列番号2または配列番号3の配列からなり、それによって前記対象の組織における細胞外マトリクス内の線維性物質の過度の蓄積を防ぐか、または減らす、医薬組成物。
- 薬学的に許容可能な担体をさらに含む、請求項12〜19のいずれか1項に記載の医薬組成物。
- 前記医薬組成物が、局所的な塗布、注射、経口投与、または持続放出投薬のために好適である、請求項12〜20のいずれか1項に記載の医薬組成物。
- 前記対象が、哺乳動物である、請求項12〜21のいずれか1項に記載の医薬組成物。
- 前記対象が、ヒトである、請求項12〜22のいずれか1項に記載の医薬組成物。
- α2ヘリックス、B−Cループ、およびα2−α3ループの領域中のβAドメインにおいてαvβ3インテグリンに特異的に結合するポリペプチドであって、前記ポリペプチドが、野生型細胞接着性タンパク質のドメイン1(D1−CD2)のバリアントを含み、前記バリアントが、配列番号2または配列番号3の配列からなる、単離されたポリペプチド。
- KDが、約1μM〜1pMである、請求項24に記載のペプチド。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562129499P | 2015-03-06 | 2015-03-06 | |
US62/129,499 | 2015-03-06 | ||
PCT/US2016/021037 WO2016144815A1 (en) | 2015-03-06 | 2016-03-04 | Integrin-targeting protein and methods of use thereof |
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JP6789961B2 true JP6789961B2 (ja) | 2020-11-25 |
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JP2023052154A (ja) | 2023-04-11 |
RU2017135220A3 (ja) | 2019-07-24 |
JP2018510861A (ja) | 2018-04-19 |
RU2017135220A (ru) | 2019-04-05 |
CN107709354B (zh) | 2022-01-04 |
AU2020280987A1 (en) | 2021-01-07 |
EP3265482A4 (en) | 2018-11-21 |
WO2016144815A1 (en) | 2016-09-15 |
US20180044403A1 (en) | 2018-02-15 |
CA2978597A1 (en) | 2016-09-15 |
JP2021046402A (ja) | 2021-03-25 |
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