JP2017052783A - アロディニア、痛覚過敏、自発痛及び幻肢痛の処置 - Google Patents
アロディニア、痛覚過敏、自発痛及び幻肢痛の処置 Download PDFInfo
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Abstract
【解決手段】以下の群から選択されるアミノ酸配列からなるポリペプチドを含む医薬。i)シグナルペプチドを欠いたヒトメテオリンタンパク質、及びii)該タンパク質のアミノ酸配列の生物学的に活性な配列バリアント、ここで、当該バリアントは、該タンパク質と少なくとも90%の配列同一性を有し、当該生物学的活性は神経栄養性の活性である。好ましい態様においては、処置される障害は、アロディニア及び痛覚過敏であり、より好ましくは、温熱及び接触性アロディニアなどのアロディニアである。
【選択図】図1
Description
i. 配列番号3のアミノ酸配列;
ii. 配列番号3のアミノ酸配列の生物学的に活性な配列バリアント、ここで、当該バリアントは配列番号3と少なくとも70%の配列同一性を有する;及び
iii. i)又はii)の少なくとも50個の近接するアミノ酸からなる生物学的に活性な断片、ここで、当該断片は配列番号3に対して少なくとも70%同一である。
i. 配列番号3のアミノ酸配列;
ii. 配列番号3のアミノ酸配列の生物学的に活性な配列バリアント、ここで、当該バリアントは配列番号3と少なくとも70%の配列同一性を有する;及び
iii. i)又はii)の少なくとも50個の近接するアミノ酸からなる生物学的に活性な断片、ここで、当該断片は配列番号3に対して少なくとも70%同一である。
i. 生体適合性の外膜及び内核、
ii. 前記内核は本件発明の細胞を含む、
iii. 前記細胞は本件発明のベクターを含む。
i. 本件発明の単離されたポリペプチド;又は
ii. 本件発明の単離された核酸;又は
iii. 本件発明の発現ベクター;又は
iv. 本件発明の株化細胞;又は
v. 本件発明の埋め込み型生体適合性カプセル;
アロディニア、痛覚過敏、自発痛及び/又は幻肢痛を処置する方法に使用するための組成物に関する。
i. 本件発明の単離されたポリペプチド;
ii. 本件発明の単離された核酸;
iii. 本件発明の発現ベクター;
iv. 本件発明の株化細胞;及び
v. 本件発明の埋め込み型生体適合性カプセル;
のアロディニア、痛覚過敏、自発痛及び/又は幻肢痛を処置するための医薬の製造における使用に関する。
●機械的アロディニア(接触性アロディニアとしても知られる)
○静的機械的アロディニア ― 軽い接触/圧力に応答する疼痛
○動的機械的アロディニア ― ブラッシングに応答する疼痛
●温熱(高温又は低温)アロディニア ― 発症領域における通常は穏やかな皮膚温度による疼痛
注射(これは、皮下、静脈内、動脈内、筋肉内、髄腔内、または他の適した部位の何れでも良い);
ポンプ(例えば、Annals of Pharmacotherapy, 27:912 (1993); Cancer, 41:1270 (1993); Cancer Research, 44:1698 (1984)、参照、本明細書に参照として取り込む)、
マイクロカプセル化(例えば、アメリカ合衆国特許4,352,883; 4,353,888;及び5,084,350、参照、本明細書に参照として取り込む)、
緩慢放出ポリマー移植片(例えば、Sabel、アメリカ合衆国特許4,883,666, 参照、本明細書に参照として取り込む)、
被包性細胞(「生体適合性カプセル」の欄を参照)、
カプセルに入っていない細胞移植片(例えば、アメリカ合衆国特許5,082,670及び5,618,531、参照、いずれも本明細書に参照として取り込む);及び
吸入。
a) 配列番号3、6及び9からなる群から選択されるアミノ酸配列;
b) 配列番号3、6及び9からなる群から選択されるアミノ酸配列の生物学的に活性な配列バリアント、ここで、当該バリアントは当該配列番号と少なくとも70%の配列同一性を有する;及び
c) a)又はb)のいずれかの少なくとも50個の近接するアミノ酸からなる生物学的に活性な断片、ここで、当該断片は当該配列番号に対して少なくとも70%同一である。
i) 配列番号2のAA30-AA288、及び一方又は両方の末端において一から五個の余分な天然配列のアミノ酸を有する配列番号2のAA25-AA293までのポリペプチド;
ii) 配列番号8のAA28-AA286、及び一方又は両方の末端において一から五個の余分な天然配列のアミノ酸を有する配列番号8のAA23-AA291までのポリペプチド;
iii) 配列番号5のAA31-AA289、及び一方又は両方の末端において一から五個の余分な天然配列のアミノ酸を有する配列番号5のAA26-AA294までのポリペプチド;及び
iv) 前記ポリペプチドのバリアント、ここで、当該選択された配列において特定される任意のアミノ酸は、異なるアミノ酸に変更される、ただし、当該配列中のアミノ酸残基は20を超えて変更されない。
-S,T,A; N,E,Q,K; N,H,Q,K; N,D,E,Q; Q,H,R,K; M,I,L,V; M,I,L,F; H,Y; F,Y,W。
-C,S,A; A,T,V; S,A,G; S,T,N,K; S,T,P,A; S,G,N,D; S,N,D,E,Q,K; N,D,E,Q,H,K; N,E,Q,H,R,K; V,L,I,M; H,F,Y。
i. 配列番号3のアミノ酸配列;
ii. 配列番号3のアミノ酸配列の生物学的に活性な配列バリアント、ここで、当該バリアントは配列番号3と少なくとも70%の配列同一性を有する;及び
iii. i)又はii)の少なくとも50個の近接するアミノ酸からなる生物学的に活性な断片、ここで、当該断片は配列番号3に対して少なくとも70%同一である。
i) 配列番号2のAA30-AA288、及び一方又は両方の末端において一から五個の余分な天然配列のアミノ酸を有する配列番号2のAA25-AA293までのポリペプチド;
ii) 配列番号8のAA28-AA286、及び一方又は両方の末端において一から五個の余分な天然配列のアミノ酸を有する配列番号8のAA23-AA291までのポリペプチド;
iii) 配列番号5のAA31-AA289、及び一方又は両方の末端において一から五個の余分な天然配列のアミノ酸を有する配列番号5のAA26-AA294までのポリペプチド;及び
iv) 前記ポリペプチドのバリアント、ここで、当該選択された配列において特定される任意のアミノ酸は、異なるアミノ酸に変更される、ただし、当該配列中のアミノ酸残基は20を超えて変更されない。
a) 配列番号1、4、7及び10からなる群から選択されるヌクレオチド配列;
b) 配列番号1、4、7及び10からなる群から選択されるヌクレオチド配列に対して少なくとも70%の配列同一性を有するヌクレオチド配列;及び
c) 配列番号1、4、7及び10からなる群から選択される配列の少なくとも150個の近接するヌクレオチドからなる核酸配列。
Claims (72)
- 以下の群から選択されるアミノ酸配列を含む、アロディニア、痛覚過敏、自発痛及び/又は幻肢痛を処置する方法に使用するための単離されたポリペプチド:
i. 配列番号3のアミノ酸配列;
ii. 配列番号3のアミノ酸配列の生物学的に活性な配列バリアント、ここで、当該バリアントは配列番号3と少なくとも70%の配列同一性を有する;及び
iii. i)又はii)の少なくとも50個の近接するアミノ酸からなる生物学的に活性な断片、ここで、当該断片は配列番号3に対して少なくとも70%同一である。 - 当該ポリペプチドが、配列番号3の配列を有するタンパク質に対して少なくとも70%、より好ましくは少なくとも75%、より好ましくは少なくとも80%、より好ましくは少なくとも85%、より好ましくは90%、より好ましくは95%、より好ましくは98%の配列同一性を有する、請求項1に記載のポリペプチド。
- 当該神経栄養性ポリペプチドが配列番号11のコンセンサス配列を含む、請求項1又は2のいずれかに記載のポリペプチド。
- 当該神経栄養性ポリペプチドが配列番号3のアミノ酸配列に関して7、28、59、95、148、151、161、219、243、及び265の位置にシステイン残基を有する、請求項1〜3のいずれか1項に記載のポリペプチド。
- 本明細書に記載されるバリアントポリペプチドであり、任意のアミノ酸置換が保存的置換である、請求項1〜4のいずれか1項に記載のポリペプチド。
- 少なくとも一つの分子内システインブリッジを形成することができる、請求項1〜5のいずれか1項に記載のポリペプチド。
- 当該処置が、少なくとも一部の処置を受けた被験対象において、実質的に完全なアロディニア、痛覚過敏、自発痛又は幻肢痛の回復を生じる、請求項1〜6のいずれか1項に記載のポリペプチド。
- 当該処置は、少なくとも一部の処置を受けた被験対象において疾患改変を生じる、請求項1〜7のいずれか1項に記載のポリペプチド。
- アロディニア及び/又は痛覚過敏を処置する方法に使用するための、請求項1〜8のいずれか1項に記載のポリペプチド。
- 当該アロディニアが温熱アロディニアである、請求項1〜9のいずれか1項に記載のポリペプチド。
- 当該アロディニアが低温アロディニアである、請求項1〜10のいずれか1項に記載のポリペプチド。
- 当該アロディニアが熱アロディニアである、請求項1〜11のいずれか1項に記載のポリペプチド。
- 当該アロディニアが機械的アロディニアである、請求項1〜12のいずれか1項に記載のポリペプチド。
- 当該処置が自発痛のためのものである、請求項1〜13のいずれか1項に記載のポリペプチド。
- 当該処置が痛覚過敏のためのものである、請求項1〜14のいずれか1項に記載のポリペプチド。
- 当該痛覚過敏が温熱性痛覚過敏である、請求項1〜15のいずれか1項に記載のポリペプチド。
- 当該痛覚過敏が低温痛覚過敏である、請求項1〜16のいずれか1項に記載のポリペプチド。
- 当該痛覚過敏が熱痛覚過敏である、請求項1〜17のいずれか1項に記載のポリペプチド。
- 当該痛覚過敏が機械的痛覚過敏である、請求項1〜18のいずれか1項に記載のポリペプチド。
- 当該処置すべき被験対象が体重減少を経験しない、請求項1〜19のいずれか1項に記載のポリペプチド。
- 当該処置すべき被験対象が哺乳動物、好ましくは霊長類、より好ましくはヒトである、請求項1〜20のいずれか1項に記載のポリペプチド。
- 全身投与によって投与される、請求項1〜21のいずれか1項に記載のポリペプチド。
- 当該処置が非経口的注射、好ましくは皮下注射、又は髄腔内注射によって投与されるものである、請求項1〜22のいずれか1項に記載のポリペプチド。
- 当該処置が、1μg/kg体重〜10,000μg/kg体重、例えば1μg/kg体重〜7,500μg/kg体重、例えば1μg/kg体重〜5,000μg/kg体重、例えば1μg/kg体重〜2,000μg/kg体重、例えば1μg/kg体重〜1,000μg/kg体重、例えば1μg/kg体重〜700μg/kg体重、例えば5μg/kg体重〜500μg/kg体重、例えば10μg/kg体重〜100μg/kg体重の投与量で投与されるものである、請求項1〜23のいずれか1項に記載のポリペプチド。
- 当該投与が毎日反復される、請求項1〜24のいずれか1項に記載のポリペプチド。
- 当該投与が毎週少なくとも1〜3回、例えば毎週2〜5回、例えば毎週3〜6回反復される、請求項1〜25のいずれか1項に記載のポリペプチド。
- 請求項1〜26のいずれか1項に記載されたポリペプチドをコードする核酸配列を含む、アロディニア、痛覚過敏、自発痛及び/又は幻肢痛を処置する方法に使用するための単離された核酸分子。
- 当該核酸分子がアロディニア及び/又は痛覚過敏を処置する方法に使用するためのものである、請求項27に記載の核酸分子。
- 請求項1〜26のいずれか1項に記載のポリペプチドをコードするポリヌクレオチドを含む、アロディニア、痛覚過敏、自発痛及び/又は幻肢痛を処置する方法に使用するためのベクター。
- 当該核酸分子に動作可能に連結されたプロモーターを更に含む、請求項29に記載のベクター。
- 当該ベクターがアルファウイルス、アデノウイルス、アデノ随伴ウイルス、バキュロウイルス、単純ヘルペスウイルス、コロナウイルス、ウシパピローマウイルス、及びMo-MLVからなる群から選択され、好ましくはアデノ随伴ウイルスである、請求項29又は30に記載のベクター。
- 当該ベクターがアロディニア及び/又は痛覚過敏を処置する方法に使用するためのものである、請求項29〜31のいずれか1項に記載のベクター。
- 請求項29〜32のいずれか1項に記載のベクターで形質転換又は形質導入された、アロディニア、痛覚過敏及び/又は自発痛を処置する方法に使用するための単離された株化細胞。
- 当該細胞がヒト細胞である、請求項33に記載の株化細胞。
- 当該株化細胞が、不死化網膜色素上皮細胞、不死化ヒト線維芽細胞、不死化ヒトアストロサイト、ヒト神経幹細胞又は前駆体細胞、ヒトグリア幹細胞又は前駆体細胞、及び胎生幹細胞などの幹細胞からなる群から選択される、請求項34に記載の株化細胞。
- 当該株化細胞がARPE-19細胞である、請求項34に記載の株化細胞。
- 当該株化細胞が、アロディニア及び/又は痛覚過敏を処置する方法に使用するためのものである、請求項33〜36のいずれか1項に記載の株化細胞。
- 分泌された生物学的に活性なメテオリンを被験対象に送達することによってアロディニア、痛覚過敏、自発痛及び/又は幻肢痛を処置する方法に使用するための、以下を含む埋め込み型生体適合性カプセル:
i. 生体適合性の外膜及び内核、
ii. 前記内核は請求項33〜37のいずれか1項に記載の細胞を含む。 - 当該生体適合性膜が、当該化合物の通過を許容する半透性外膜である、請求項38に記載のカプセル。
- 当該内核がマトリックスを含む、請求項38又は39に記載のカプセル。
- カプセル体積が少なくとも1μL、例えば1〜10μLのマクロカプセルである、請求項38〜40のいずれか1項に記載のカプセル。
- カプセル体積のμLあたり10,000〜250,000 細胞、より好ましくはμLあたり50,000〜200,000 細胞、より好ましくはμLあたり100,000〜200,000 細胞、より好ましくはμLあたり15,000〜50,000 細胞、より好ましくはμLあたり20,000〜30,000 細胞を含む、請求項38〜41のいずれか1項に記載のカプセル。
- 当該カプセルが、アロディニア及び/又は痛覚過敏を処置する方法に使用するためのものである、請求項38〜42のいずれか1項に記載のカプセル。
- 必要とする被験対象に対して治療的に有効な量の請求項1〜26のいずれか1項に記載の単離されたポリペプチドを投与する工程を含む、被験対象におけるアロディニア、痛覚過敏、自発痛及び/又は幻肢痛を処置するための方法。
- 当該処置が、アロディニア及び/又は痛覚過敏のためのものである、請求項44に記載の方法。
- 当該処置が、自発痛のためのものである、請求項44に記載の方法。
- 当該処置が、痛覚過敏のためのものである、請求項44に記載の方法。
- 当該痛覚過敏が、温熱性痛覚過敏である、請求項47に記載の方法。
- 当該痛覚過敏が、低温痛覚過敏である、請求項47に記載の方法。
- 当該痛覚過敏が、熱痛覚過敏である、請求項47に記載の方法。
- 当該痛覚過敏が、機械的痛覚過敏である、請求項47に記載の方法。
- 当該処置すべき被験対象が、体重減少を経験しない、請求項44に記載の方法。
- 当該処置すべき被験対象が、哺乳動物、好ましくは霊長類、より好ましくはヒトである、請求項44に記載の方法。
- 当該処置が、全身投与によって投与されるものである、請求項44に記載の方法。
- 当該処置が、非経口的注射、好ましくは皮下注射、又は髄腔内注射によって投与されるものである、請求項44に記載の方法。
- 当該処置が、1μg/kg体重〜10,000μg/kg体重、例えば1μg/kg体重〜7,500μg/kg体重、例えば1μg/kg体重〜5,000μg/kg体重、例えば1μg/kg体重〜2,000μg/kg体重、例えば1μg/kg体重〜1,000μg/kg体重、例えば1μg/kg体重〜700μg/kg体重、例えば5μg/kg体重〜500μg/kg体重、例えば10μg/kg体重〜100μg/kg体重の投与量で投与されるものである、請求項44に記載の方法。
- 当該投与が、毎日反復される、請求項44に記載の方法。
- 当該投与が、毎週少なくとも1〜3回、例えば毎週2〜5回、例えば毎週3〜6回反復される、請求項44に記載の方法。
- 当該処置が、少なくとも一部の処置を受けた被験対象において、実質的に完全なアロディニア、痛覚過敏、自発痛又は幻肢痛の回復を生じる、請求項44に記載の方法。
- 当該処置が、少なくとも一部の処置を受けた被験対象において疾患改変を生じる、請求項44に記載の方法。
- 以下の工程を含む、必要とするヒト被験対象において神経障害性疼痛を処置する方法、に使用するための神経栄養性メテオリンポリペプチド: 治療的に有効な量の神経栄養性ポリペプチドを当該被験対象に投与する工程、ここで、当該ポリペプチドは配列番号3のアミノ酸配列と少なくとも70%の同一性を有するアミノ酸配列であり、当該投与は週三回又はより頻度が低い。
- 当該投与は毎週の又はより低い頻度の投与である、請求項61に記載のポリペプチド。
- 当該投与は隔週の又はより頻度が低い投与である、請求項61に記載のポリペプチド。
- 前記処置の治療効果は、ポリペプチド投与の間の期間全体にわたって、神経障害性疼痛の少なくとも一つの症状を寛解させる、請求項61に記載のポリペプチド。
- 当該症状が、アロディニア、痛覚過敏、自発痛、幻肢痛、燃焼、刺痛、電気、ピン及び針の感覚、錯感覚、異常感覚、硬直、四肢の痺れ、体捻挫感、及びヒペルパチーからなる群から選択される、請求項64に記載のポリペプチド。
- 前記処置によって、ポリペプチド投与の間の期間全体にわたって、前記被験対象の血清中の前記ポリペプチドは測定可能なレベルに維持されない、請求項61に記載のポリペプチド。
- 前記被験対象の血清中の前記ポリペプチドのレベルは、ポリペプチド投与の間で、10 ng/mLより低い、請求項66に記載のポリペプチド。
- 以下の工程を含む、必要とするヒト被験対象において神経障害性疼痛を処置する方法、に使用するための神経栄養性メテオリンポリペプチド: 治療的に有効な量の神経栄養性ポリペプチドを当該被験対象に投与する工程、ここで、当該ポリペプチドは配列番号3のアミノ酸配列と少なくとも70%の同一性を有するアミノ酸配列であり、ここで、前記処置によって、ポリペプチド投与の間隔全体にわたって、前記被験対象の血清中の前記ポリペプチドは測定可能なレベルに維持されない。
- 前記被験対象の血清中の前記ポリペプチドのレベルは、ポリペプチド投与の間で、10 ng/mLより低い、請求項68に記載のポリペプチド。
- 当該ポリペプチドが、配列番号3の配列を有するタンパク質に対して少なくとも75%、より好ましくは少なくとも80%、より好ましくは少なくとも85%、より好ましくは90%、より好ましくは95%、より好ましくは98%の配列同一性を有する、請求項61〜69のいずれか1項に記載のポリペプチド。
- 当該神経栄養性ポリペプチドが配列番号11のコンセンサス配列を含む、請求項61〜70のいずれか1項に記載のポリペプチド。
- 当該神経栄養性ポリペプチドが配列番号3のアミノ酸配列に関して7、28、59、95、148、151、161、219、243、及び265の位置にシステイン残基を有する、請求項61〜70のいずれか1項に記載のポリペプチド。
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CN103269708A (zh) | 2013-08-28 |
CA2813013A1 (en) | 2012-04-05 |
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US9314502B2 (en) | 2016-04-19 |
WO2012041328A1 (en) | 2012-04-05 |
KR101886029B1 (ko) | 2018-08-07 |
HK1186412A1 (zh) | 2014-03-14 |
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EP2621512B1 (en) | 2016-04-06 |
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US8404642B2 (en) | 2013-03-26 |
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JP6247734B2 (ja) | 2017-12-13 |
EP2621512A1 (en) | 2013-08-07 |
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US20150202262A1 (en) | 2015-07-23 |
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