JP2016539188A - 新規カベオリンモジュレーターを使用する自己免疫および/または炎症疾患の治療 - Google Patents
新規カベオリンモジュレーターを使用する自己免疫および/または炎症疾患の治療 Download PDFInfo
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Abstract
Description
本出願は、2013年11月26日に出願された米国仮特許出願第61/909,005号の優先権の恩典を主張する。
本開示は新規組成物およびそのような組成物を使用して、自己免疫および/または炎症疾患/病状を治療および/または防止するための方法に関する。
本明細書で使用される略語は、化学および生物学分野内のそれらの従来の意味を有する。
本明細書で記載するように、短い5−アミノ酸ペプチド(RRPPR−SEQ ID NO.1)であるEndo5は非常に強力な細胞透過性ペプチド(CPP)である。Endo5は、血管内皮細胞により迅速にインターナライズされるその能力に対する競合的選択プロセスにより単離され、細胞によるカーゴ取込を増大し、かつそれがコンジュゲートされるカーゴの治療活性を増大することが示された。
本明細書で記載される発明は、カーゴ部分を標的細胞に、または標的細胞中に送達する方法を含む。1つの実施形態では、方法は、標的細胞を輸送コンストラクトと接触させることを含み、輸送コンストラクトはカーゴ部分およびアミノ酸配列SEQ ID NO.1を含む輸送ペプチドを含み、これによりカーゴ部分は標的細胞に、または標的細胞中に送達される。
様々な実施形態では、本明細書で記載される組成物は、1つ以上の自己免疫疾患を治療するのに有用である。
様々な実施形態では、本明細書で記載される組成物は、1つ以上の炎症疾患または障害を治療または防止するのに有用である。
ぶどう膜炎は米国の50万を超える人々に影響を与え、その慢性形態は5−20%の失明をもたらす。急性炎症過程および進行性視力喪失の両方を低減させるために、ぶどう膜炎のためのより良好な療法が必要とされる。特に、現在の療法と関連する重大な認容性の問題なしに、炎症および視力喪失を低減させる療法は、ぶどう膜炎患者に対し短期および長期の両方で視力を改善させるであろう。
炎症疾患の別の例は多発性硬化症(MS)である。MSはCNSの慢性で予測不可能な炎症疾患であり、脳および脊髄に影響を与える可能性があり、一般に若年成人に影響する。Hafler et al. (2005) Immunol Rev 204:208−31。現在のところ、若年成人の最も一般的な神経疾患であるといわれており、通常20歳〜40歳の間で始まり、男性と比べてほぼ2倍の確率で女性に起こる傾向がある。
外傷性脳損傷(TBI)または神経外傷は、米国および世界中での多くの死亡および永久的な能力障害の症例の一因である。米国で毎年、TBIにかかっている140万の人々のうち、50,000人が死亡し、235,000人が入院し、別の110万人が治療され、救急部から退出する。米国では0〜14歳の子供のうち、TBIにより、毎年435,000人が救急部を訪れ、2,685人が死亡し、37,000人が入院している。Langlois se al, Traumatic brain injury in the United States: emergency department visits, hospitalizations, and deaths, Atlanta (Ga.): Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2004。
様々な実施形態では、本明細書で提供される組成物は、炎症性腸疾患の治療のために有用である。特定の実施形態では、炎症性腸疾患は潰瘍性大腸炎またはクローン病である。
本発明内の有用な組成物は、発明内で企図される疾患または障害を治療するために有用な1つ以上の追加の化合物と組み合わせて、本発明の方法内で有用であることが意図される。これらの追加の化合物は、本発明の化合物または発明内で企図される疾患または障害の症状を治療、防止、または低減させることが知られている化合物、例えば、市販の化合物を含み得る。
投与レジメンは、何が有効量を構成するかに影響し得る。治療製剤は、疾患または障害の発症の前または後のいずれかで患者に投与され得る。さらに、複数に分割された投与量、ならびに時差投与量が毎日または順次投与され得、または用量は連続して注入され得、またはボーラス注射であってもよい。さらに、治療製剤の投与量は、治療的または予防的状況の要件により示されるように、比例的に増加または減少させてもよい。
経口適用のためには、錠剤、糖衣錠、液体、ドロップ、坐薬、またはカプセル、カプレットおよびジェルキャップが特に好適である。経口使用のために意図される組成物は、当技術分野で知られている任意の方法により調製でき、そのような組成物は、錠剤の製造に好適な、不活性で無毒性の医薬賦形剤からなる群より選択される1つ以上の作用物質を含み得る。そのような賦形剤としては、例えば、ラクトースなどの不活性希釈剤;コーンスターチなどの造粒および崩壊剤;デンプンなどの結合剤;およびステアリン酸マグネシウムなどの潤滑剤が挙げられる。錠剤は無コートでもよく、または、正確さのためにまたは活性成分の放出を遅延させるための公知の技術によりコートしてもよい。経口使用のための製剤はまた、ハードゼラチンカプセルとして提供でき、この場合、活性成分は不活性希釈剤と混合される。
非経口投与のために、化合物は、注射または注入、例えば、静脈内、筋肉内または皮下注射または注入のために、あるいは急速投与量および/または持続注入での投与のために製剤化されてもよい。懸濁、安定および/または分散剤などの他の調合剤を任意に含む、油性または水性ビヒクル中の溶液、懸濁液またはエマルジョンが使用され得る。
この発明の追加の剤形は、下で記載される剤形を含む:米国特許第6,340,475号、6,488,962号、6,451,808号、5,972,389号、5,582,837号、および5,007,790号。この発明の追加の剤形はまた、下で記載される剤形を含む:米国特許出願第2003/0147952号、2003/0104062号、2003/0104053号、2003/0044466号、2003/0039688号、および2002/0051820号。この発明の追加の剤形はまた、下で記載される剤形を含む:PCT出願第WO03/35041号、WO03/35040号、WO03/35029号、WO03/35177号、WO03/35039号、WO02/96404号、WO02/32416号、WO01/97783号、WO01/56544号、WO01/32217号、WO98/55107号、WO98/11879号、WO97/47285号、WO93/18755号、およびWO90/11757号。
ある実施形態では、本発明の製剤は、短期の、迅速消失性の、ならびに制御された、例えば、徐放の、遅延放出のおよびパルス放出の製剤であってよいが、それらに限定されない。
化合物の治療的有効量または用量は、患者の年齢、性別および体重、患者の現在の医学的状態および治療されている患者における疾患/障害の進行に依存するであろう。当業者は、これらのおよび他の因子によって適切な投与量を決定できるであろう。
発明を以下の実施例を参照して説明する。これらの実施例は、説明の目的のためだけに提供され、発明はこれらの実施例に制限されず、むしろ、本明細書で提供される教示の結果明らかになる全てのバリエーションを包含する。
培養したラット心臓毛細血管内皮細胞(RHMVEC)を、VEC Technologies(Rensselaer、NY)から購入し、フィブロネクチンコートプレート上で、MCDB−131完全培地(VEC Technologies)にて増殖させた。BAECを地方の屠殺場から得られたウシ大動脈から単離し、10%FBS(Hyclone)およびpen/strepが補充されたDMEM(高グルコース;Cellgro)中で増殖させた。ヒト臍血管内皮細胞(HUVEC)を、ヒト臍帯から局所的に単離し、内皮細胞増殖サプリメント(Invitrogen)、10%FBS、L−グルタミン(Invitrogen)およびpen/strepが補充されたM199培地(Invitrogen)中で増殖させた。
Novagen T7 selectファージディスプレイシステムを、内皮細胞取込を促進するペプチドのランダムスクリーニングのために、7−merペプチドをランダムにコードするオリゴヌクレオチドのプールと併せて、使用した。HindIII/XhoI部位を含む7−merランダムペプチドプライマーを下記の通りに設計した:
センスプライマー:
5’−GCTAGAATTCNNNBNNBNNBNNBNNBNNBNNBAAGCTTACTGCAGTAGCATG−3’、ここで、N=A、T、C、G;およびB=G、C、T(SEQ ID NO.9);
アンチセンスプライマー:
5’−CATGCTACTGCAGTAAGCTT−3’(SEQ ID NO.10)。
ラット心臓毛細血管内皮細胞(RHMVEC)(80%コンフルエント;およそ2×107細胞/100mmディッシュ)をリン酸緩衝溶液(PBS)で洗浄し、無血清培地中、37℃で30分間プレインキュベートし、T7ファージライブラリ抽出物(5×l09pfu)を接種し、250の感染多重度(MOI)に到達させた。1時間の37℃でのインキュベーション後、細胞を、氷冷PBSで洗浄し、0.1N HCl、pH2.2で15秒間酸洗浄して未結合の、および弱く結合したファージを細胞表面から除去した。
それらのC末端に融合されるカーゴ(DGIWKASFTTFTVTKYWFYR)(SEQ ID NO.5)を有する、または有さないEndo5(RRPPR)(SEQ ID NO.1)またはアンテナペディア(RQIKIWFQNRRMKWKK)(SEQ ID NO.2)に対応するペプチドを、イェール大学医学大学院のW.M.Keckバイオテクノロジー資源センターにより、標準Fmoc化学により合成し、質量分析により分析し純度を確認した。フルオロフォア(Endo5に対してはカルボキシフルオセインおよびAPに対してはローダミン)を、合成後にN末端に付加した。
VEGF誘導性NO放出実験を、前に記載されるように実施した。簡単に言うと、コンフルエントBAECを無血清DMEM中で6時間ペプチドと共にインキュベートした。培地を除去し、新鮮な無血清DMEMを、VEGF(10−9M)と共に、またはなしで30分間添加した。培地を収集し、細胞をトリプシン処理し、計数し、上清中の亜硝酸レベルをSievers NO化学ルミネセンス分析計を用いることにより決定した。
マウス皮膚における血漿漏出を、マイルスアッセイを用いて前に記載されるように検討した。簡単に言うと、雄Swissマウス(30−35g)に麻酔をかけ、エバンスブルー(PBS溶液中30mg/kg;Sigma)を注射した。フェニルイソチオシアネート(鉱物油中5%)、カラシ油の類似体(Pierce、Rockford、Illinois)を、右耳に、綿棒で適用した。
培養したBAECを6−ウェルプレートでコンフルエンスに到達するまで増殖させた。細胞を洗浄し、標識ペプチド(10−6M)を含む1mLのDMEM中で1、2、4または6時間、37℃でインキュベートし、0.1Mグリシンを含む冷PBS(pH4)で3回洗浄して非特異的表面染色を除去した。
新しく単離したHUVECを、ガラス底を有するペトリ皿上の、グルタミン、10%FBSおよび内皮細胞増殖サプリメントが補充されたM199培地中で増殖させた。CPPは非特異的にガラスへ結合するので、ガラス底ペトリ皿を未標識APおよびEndo5を含むブロッキング溶液で30分間(5×10−5M)、1%FBSを有する無色M199培地中にて前処理することにより、バックグラウンド蛍光を低減した。
カプシド上に平均0.1〜1コピーのランダムに生成された7−merペプチドを発現する、T7ファージディスプレイライブラリを作成した。一定量のインプットファージ(5×109)を、培養したラット心臓毛細血管内皮細胞(RHMVEC)に添加し、これらのファージを、細胞単層により迅速にインターナライズされる(細胞取込)それらの能力について選択した。
AP−Cavは、培養内皮細胞においてアゴニスト誘導性eNOS活性をブロックし(Bucci et al., 2000, Nat. Med. 6: 1362−7)、この生物活性は、AP−Cavのインターナリゼーション、投与量および前処理時間に依存する。本明細書で記載される研究では、Endo5の取込可能性を、培養したBAECによるNO放出に関するCavに融合したEndo5(endo5−Cav)の効果を試験することにより、APのそれと比較した。
EC誘導性NO生成は、炎症において、一つには、毛細管内圧力の増加およびその後の血管透過性を促進することにより積極的役割を果たす。マウスのAP−Cavによる前処置は、マイルスアッセイにおいて血管漏出をブロックする(Bucci et al., 2000, Nat. Med. 6: 1362−7; Bernatchez et al, 2005, Proc. Natl. Acad. Sci. USA 102:761−6)。この確立されたモデルはしたがって、Endo5−融合ペプチドのインビボ効力を評価するための有用なツールとなり得る。図3Aおよび3Bは、Endo5−Cav(SEQ ID NO.1/SEQ ID NO.5)がインビボでエバンスブルー血管外漏出をブロックすることを証明する。
APは、ニューロンの膜を横断するCPPである。Joliot et al., 1991, Proc. Natl. Acad. Sci. U S A 88: 1864−8。本明細書の他のどこかで記載されるように、Endo5は内皮細胞におけるファージの高いインターナリゼーションを促進することが予想外に見出され、Endo5−Cavは、eNOS活性化および血管透過性の防止について、AP−Cavよりも強力であることが予想外に見出された。
細胞内へのCPP移行に関与する取込メカニズムを明らかにすることを試みた以前の研究では、イメージングが固定した細胞中で実施された。これらの研究の結果は、細胞固定がCPPの予想外の核移行を引き起こすという山のような証拠を考慮すると、信頼できない可能性がある。Richard et al, 2003, J. Biol. Chem. 278:585−90。
レーザー誘起した新血管新生のラットモデルにおける、硝子体内注射に関するカブトラチンの分析。このモデルでは、カブトラチンを4日間隔で2回投与し、第8日に評価した。この研究からの結果を、図6で提供する。
(1)カブトラチン(2.5mg/kg)による治療対未処置対照。これにより、カベオリン機能の阻害が炎症を寛解させることを確認する。治療は、2つの群の病理組織学的スコア間に差がある場合に、成功と判断される。群間で、統計的に有意でない大きな差がある場合、有意性を達成するために数を増加させることが考えられる。平均値間に少なくとも25%の差があるが統計学的有意性がない場合、より高い用量のカブトラチンを使用して実験が繰り返される。
(2)Endo5−CavAB(SEQ ID NO.1/SEQ ID NO.6)よる治療(用量反応曲線、0.3、1.0、および3.0mg/kg用量を使用)対未処置対照。0.3mg/kg用量が、未免疫対照と統計的に差のない効果を生成する場合、より低い用量が、0.1、0.03、0.01mg/kgの順で、効果レベルが未免疫対照動物スコアと異なるまで使用される。最大効果を生成するEndo5−CavAB(SEQ ID NO.1/SEQ ID NO.6)の用量が同定された時に、研究が完了する。
(3)最適用量のEndo5−CavAB(SEQ ID NO.1/SEQ ID NO.6)対ペプチドの細胞透過性フラグメントのみを含む対照ペプチドによる治療。この群を用いて用量応答実験を確認する。Endo5−CavAB(SEQ ID NO.1/SEQ ID NO.6)の最適用量がいったん同定されると、最適用量Endo5−CavAB(SEQ ID NO.1/SEQ ID NO.6)対カブトラチン対未処置対照の比較がなされる。この最後の比較が免疫組織化学のための固定により繰り返され、目が抗マウスCD45で染色され、およびCD45+細胞により網膜の侵襲が定量化される。
ウサギ毒性学。このシリーズの目的は、薬物自体が、ぶどう膜炎モデルを妨害するいずれの毒性効果も動物において生成させないことを保証することである。第2の目的は、我々が使用するものより高い用量が毒性効果を有さず、治療濃度域が存在することを確立することである。
ぶどう膜炎モデルは、Rosenbaum/Lin研究所において既存のプロトコルによって実施される。1つの目のみに免疫原が注射されてぶどう膜炎を誘導し、その目だけに薬物が注射される。薬物の少なくとも2つの用量が硝子体内で試験される。各用量で、薬物が第0日および第3日に投与され、第6日に屠殺される。終点(一次)は細胞であり、臨床スコアリングを有する房水中のタンパク質が二次である。細胞は細胞計数器(コールターカウンター)または血球計数器のいずれかを使用して計数される。
穿通性および閉鎖性頭部外傷の両方を含む外傷性脳損傷、ならびに脊髄への損傷は、炎症性要素を有することが長く認識されている。例えば、Hernandez−Ontiveros DG, Tajiri N, Acosta S, Giunta B, Tan J, Borlongan CV. Microglia activation as a biomarker for traumatic brain injury. Frontiers in neurology. 2013; 4:30 doi: 10.3389/fneur.2013.00030. PubMed PMID: 23531681; PubMed Central PMCID: PMC3607801を参照されたい。
クローン病および潰瘍性大腸炎を含む炎症性腸疾患(IBD)は、腸管の炎症疾患である。IBDの多くのモデルが存在し、最も一般的なのは、デキストラン硫酸ナトリウムモデルである。例えば、Koboziev et al, Pharmacological intervention studies using mouse models of the inflammatory bowel diseases: translating preclinical data into new drug therapies, Inflammatory bowel diseases. 2011; 17(5): 1229−45. doi: 10.1002/ibd.21557. PubMed PMID: 21312318; PubMed Central PMCID: PMC307537を参照されたい。このモデルは、カベオリン類似体の効力を証明するために使用される。
多発性硬化症は長く、炎症状態として認識されており、現在の治療としては、免疫抑制剤、例えばステロイド、メトトレキサート、およびインターフェロン(ベータセロン(登録商標)、アボネックス(登録商標)、など)、および最近になってジレニア(登録商標)(フィンゴリモド)が挙げられる。
Claims (39)
- アミノ酸配列RRPPR(SEQ ID NO.1)を含む単離輸送ペプチドを含む組成物を投与することを含む、被験体において炎症疾患または病状を治療するための方法。
- 前記炎症疾患または病状はぶどう膜炎、多発性硬化症、視神経脊髄炎、外傷性脳損傷または炎症性腸疾患である、請求項1に記載の方法。
- 前記輸送ペプチドはSEQ ID NO.1からなる、請求項1に記載の方法。
- 前記輸送ペプチドは標的細胞に選択的に結合するまたは細胞膜を横断する、請求項1に記載の方法。
- 前記標的細胞は内皮細胞、心臓細胞、骨格筋細胞または脳細胞を含む、請求項4に記載の方法。
- 前記組成物は薬学的に許容される担体をさらに含む、請求項1に記載の方法。
- 前記組成物は輸送コンストラクトを含み、前記輸送コンストラクトはSEQ ID NO.1を含む前記輸送ペプチドに連結されたカーゴ部分を含む、請求項1に記載の方法。
- 前記輸送ペプチドはSEQ ID NO.1からなる、請求項7に記載の方法。
- 前記カーゴ部分は下記からなる群より選択される、請求項7に記載の方法:核酸;ペプチド;タンパク質;オリゴ糖;脂質;糖脂質;リポタンパク質;小分子化合物;治療薬;UV−vis、蛍光または放射性標識;造影剤;診断薬;予防薬;リポソームおよびウイルス。
- 前記カーゴ部分はリンカーまたは化学結合を介して前記輸送ペプチドに共有結合的に連結される、請求項7に記載の方法。
- 前記輸送コンストラクトは標的細胞に選択的に結合するまたは細胞膜を横断する、請求項7に記載の方法。
- 前記標的細胞は内皮細胞、心臓細胞、骨格筋細胞または脳細胞を含む、請求項11に記載の方法。
- 前記カーゴ部分はSEQ ID NO.3〜6からなる群より選択される少なくとも1つである、請求項7に記載の方法。
- 前記輸送コンストラクトは下記からなる群より選択される少なくとも1つの配列を含む、請求項13に記載の方法:SEQ ID NO.1−SEQ ID NO.3;SEQ ID NO.1−SEQ ID NO.4;SEQ ID NO.1−SEQ ID NO.5;SEQ ID NO.1−SEQ ID NO.6;SEQ ID NO.3−SEQ ID NO.1;SEQ ID NO.4−SEQ ID NO.1;SEQ ID NO.5−SEQ ID NO.1;およびSEQ ID NO.6−SEQ ID NO.1。
- 前記組成物はSEQ ID NO.1を含む輸送ペプチドをコードする核酸を含む、請求項1に記載の方法。
- 前記核酸は5’−CGGCGCCCGCCTCGT−3’(SEQ ID NO.7)を含む、請求項15に記載の方法。
- 少なくとも1つのカーゴ部分をコードする単離核酸をさらに含む、請求項15に記載の方法。
- 前記カーゴ部分は下記からなる群より選択される、請求項17に記載の方法:ペプチド;タンパク質;生物活性化合物;標識;造影剤;診断薬;治療薬;および予防薬。
- 前記カーゴ部分はSEQ ID NO.3〜6からなる群より選択される、請求項18に記載の方法。
- 薬学的に許容される担体をさらに含む、請求項15に記載の方法。
- 前記核酸は前記輸送ペプチドをコードする単離核酸である、請求項15に記載の方法。
- 前記輸送ペプチドをコードする核酸の発現を可能にする転写活性化エレメントをさらに含む、請求項15に記載の方法。
- 前記輸送ペプチドをコードする核酸とインフレームでカーゴ部分をコードする核酸をさらに含む、請求項15に記載の方法。
- 前記組成物はアミノ酸配列SEQ ID NO.1を含む輸送ペプチドをコードする外来の核酸を含む単離宿主細胞を含む、請求項1に記載の方法。
- 前記核酸は(a)前記輸送ペプチドをコードする核酸、および(b)前記輸送ペプチドをコードする核酸とインフレームでカーゴ部分をコードする核酸を含むベクターである、請求項24に記載の方法。
- 前記宿主細胞における(a)の前記核酸および(b)の前記核酸の発現を可能にする転写活性化エレメントをさらに含む、請求項25に記載の方法。
- カーゴ部分を標的細胞へまたは標的細胞中に送達することにより治療の必要な被験体を治療する方法であって、前記標的細胞を輸送コンストラクトと接触させることを含み、前記輸送コンストラクトはカーゴ部分およびアミノ酸配列SEQ ID NO.1を含む輸送ペプチドを含み、これにより前記カーゴ部分は前記標的細胞へまたは前記標的細胞中に送達される、方法。
- 前記カーゴ部分はリンカーまたは化学結合を介して前記輸送ペプチドに共有結合的に連結される、請求項27に記載の方法。
- 前記輸送ペプチドはSEQ ID NO.1からなる、請求項27に記載の方法。
- 前記カーゴ部分は下記からなる群より選択される少なくとも1つである、請求項27に記載の方法:核酸;ペプチド;タンパク質;オリゴ糖;脂質;糖脂質;リポタンパク質;小分子化合物;治療薬;UV−vis、蛍光または放射性標識;造影剤;診断薬;予防薬;リポソームおよびウイルス。
- 前記標的細胞は内皮細胞、心臓細胞、骨格筋細胞または脳細胞を含む、請求項27に記載の方法。
- カーゴ部分を治療の必要な被験体の標的細胞へまたは標的細胞中に送達する方法であって、輸送コンストラクトを含む薬学的に許容される組成物の治療的有効量を前記被験体に投与することを含み、前記輸送コンストラクトは前記カーゴ部分およびアミノ酸配列SEQ ID NO.1を含む輸送ペプチドを含み、これにより前記カーゴ部分は前記被験体の前記標的細胞へまたは前記標的細胞中に送達される、方法。
- 前記カーゴ部分はリンカーまたは化学結合を介して前記輸送ペプチドに共有結合的に連結される、請求項32に記載の方法。
- 前記輸送ペプチドはSEQ ID NO.1からなる、請求項32に記載の方法。
- 前記カーゴ部分は下記からなる群より選択される少なくとも1つである、請求項32に記載の方法:核酸;ペプチド;タンパク質;オリゴ糖;脂質;糖脂質;リポタンパク質;小分子化合物;治療薬;UV−vis、蛍光または放射性標識;造影剤;診断薬;予防薬;リポソームおよびウイルス。
- 前記標的細胞は内皮細胞、心臓細胞、骨格筋細胞または脳細胞を含む、請求項32に記載の方法。
- 前記組成物は下記からなる群より選択される少なくとも1つの経路により投与される、請求項1〜36のいずれか1項に記載の方法:静脈内、経口、吸入、直腸、腟内、経皮、鼻腔内、頬側、舌下、非経口、くも膜下腔内、胃内、眼部、肺および局所。
- 前記被験体は哺乳類である、請求項37に記載の方法。
- 前記哺乳類はヒトである、請求項38に記載の方法。
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JP2020072716A (ja) * | 2013-11-26 | 2020-05-14 | イエール ユニバーシティ | 細胞透過組成物およびそれを用いる方法 |
CN112739367A (zh) * | 2018-09-10 | 2021-04-30 | 肺疾治疗公司 | Cav-1蛋白的修饰的肽片段及其在纤维化治疗中的用途 |
JP2022500078A (ja) * | 2018-09-10 | 2022-01-04 | ラング セラピューティクス,インコーポレイテッド | Cav−1タンパク質の修飾ペプチドフラグメント及び線維症の治療におけるその使用 |
JP7496826B2 (ja) | 2018-09-10 | 2024-06-07 | ラング セラピューティクス,エルエルシー | Cav-1タンパク質の修飾ペプチドフラグメント及び線維症の治療におけるその使用 |
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ES2743622T3 (es) | 2020-02-20 |
EP3074034B1 (en) | 2019-05-01 |
EP3074034A4 (en) | 2017-06-07 |
JP6692751B2 (ja) | 2020-05-13 |
US10537607B2 (en) | 2020-01-21 |
EP3074034A2 (en) | 2016-10-05 |
WO2015080980A2 (en) | 2015-06-04 |
US20170128520A1 (en) | 2017-05-11 |
WO2015080980A3 (en) | 2015-09-11 |
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