TW202200606A - C4結合蛋白之C端片段與血管生成素-1之類纖維蛋白原結構域之間之嵌合融合作為治療血管疾病之血管生成素模擬物及Tie2促效劑 - Google Patents
C4結合蛋白之C端片段與血管生成素-1之類纖維蛋白原結構域之間之嵌合融合作為治療血管疾病之血管生成素模擬物及Tie2促效劑 Download PDFInfo
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Abstract
本發明係關於血管生成素-1模擬物,其用於經由Tie2/TEK受體之促效活化來治療血管疾病。
Description
在其他態樣中,本發明係關於血管生成素-1模擬物,其用於經由Tie2/TEK受體之促效活化來治療血管疾病。
血管生成素-Tie2信號傳導路徑為血管發育、脈管重塑、出生後血管生成及脈管滲透性之主要調節因子(Saharinen P, Eklund L, Alitalo K. Therapeutic targeting of the angiopoietin-TIE pathway. Nat Rev Drug Discov. 2017;16(9):635-661)。此路徑主要經由內皮酪胺酸激酶受體Tie2 (TEK)利用其胞外配位體血管生成素-1 (Ang1)及血管生成素-2 (Ang2)之直接結合來操作(Saharinen P, Eklund L, Alitalo K. Therapeutic targeting of the angiopoietin-TIE pathway. Nat Rev Drug Discov. 2017;16(9):635-661)。雖然充分定義Ang1之強典型促效劑功能,但Ang2通常被視為Tie2之環境依賴性拮抗劑(Souma T等人Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP. Proc Natl Acad Sci U S A. 2018;115(6):1298-1303)。另外,Ang-Tie2信號傳導之強度係藉由負調節因子,諸如血管內皮蛋白酪胺酸磷酸酶(VEPTP/PTPRB)調節,且該路徑亦具有與整合素信號傳導的串擾(Saharinen P, Eklund L, Alitalo K. Therapeutic targeting of the angiopoietin-TIE pathway. Nat Rev Drug Discov. 2017;16(9):635-661)。在Tie2下游,可活化多個胞內信號轉導路徑,從而導致ERK1/2、AKT及eNOS磷酸化(Saharinen P, Eklund L, Alitalo K. Therapeutic targeting of the angiopoietin-TIE pathway. Nat Rev Drug Discov. 2017;16(9):635-661)。
已研究血管生成素-Tie2信號傳導系統作為用於治療廣泛範圍之疾病的潛在治療目標。存在大量描述如何活化此路徑對血管滲漏及發炎具有保護作用之文獻(Parikh SM. Angiopoietins and Tie2 in vascular inflammation. Curr Opin Hematol. 2017;24(5):432-438;Saharinen P, Eklund L, Alitalo K. Therapeutic targeting of the angiopoietin-TIE pathway. Nat Rev Drug Discov. 2017;16(9):635-661)。適應症包括(但不限於)癌症、敗血症、缺血性中風、急性腎損傷、慢性腎病、糖尿病性腎病變及視網膜病變、傷口癒合、急性肺損傷、同種異體移植排斥反應以及其他疾病及病狀(Saharinen P, Eklund L, Alitalo K. Therapeutic targeting of the angiopoietin-TIE pathway. Nat Rev Drug Discov. 2017;16(9):635-661)。經由外源性干預調節此路徑提供一種藉由預防發炎及血管滲漏之有害影響來穩定血管內皮的治療機會,藉此保持內皮屏障完整性(Parikh SM. Angiopoietins and Tie2 in vascular inflammation. Curr Opin Hematol. 2017;24(5):432-438)。
學術實驗室及生物技術公司已作出大量努力以產生用於治療用途之生物等效或生物較佳的Ang類似物或模擬物。已嘗試若干Ang1模擬物設計,然而無一者達至臨床試驗階段,此主要係因在達成所需藥理學作用中所遭遇之障礙所致(Koh GY. Orchestral actions of angiopoietin-1 in vascular regeneration. Trends Mol Med. 2013;19(1):31-39)。
血管生成素共用類似分子結構域架構,該分子結構域架構具有C端類纖維蛋白原結構域(FLD)-其賦予與細胞表面受體Tie2之結合;中間捲曲螺旋結構域(CCOD)-其介導單體之均多聚化(homo-multimerization);及較短N端超叢集結構域(SCD)片段-其使得血管生成素二聚體能夠經由分子內二硫橋鍵(圖1A)叢集化為多聚結構(Koh GY. Orchestral actions of angiopoietin-1 in vascular regeneration. Trends Mol Med. 2013;19(1):31-39)。較高寡聚化為效力之主要決定因素且雖然單體血管生成素配位體可結合Tie2,但其不誘導Tie2受體酪胺酸磷酸化及調節微血管且對於血液及淋巴脈管發育、維持及功能至關重要之下游胞內信號傳導的活化(Saharinen P, Eklund L, Alitalo K. Therapeutic targeting of the angiopoietin-TIE pathway. Nat Rev Drug Discov. 2017;16(9):635-661)。Ang1為主要以高階多聚形式存在之Tie2之強效促效劑,其促進Tie2受體之叢集化且引發下游信號傳導級聯(Koh GY. Orchestral actions of angiopoietin-1 in vascular regeneration. Trends Mol Med. 2013;19(1):31-39)。高階多聚配位體為Tie2之最佳結合子,且由於親合力而強烈地誘導配位體複合之Tie2受體之酪胺酸磷酸化(Kim KT等人Oligomerization and multimerization are critical for angiopoietin-1 to bind and phosphorylate Tie2. J Biol Chem. 2005;280(20):20126-20131)。相比之下,Ang2最常以二聚體形式存在,使其在存在Ang1時為競爭性Tie2拮抗劑,但在Ang1及VE-PTP相對缺乏時為Tie2之部分促效劑,此似乎設定了Tie2對各配位體之反應性的臨限值(Souma T等人Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP. Proc Natl Acad Sci U S A. 2018;115(6):1298-1303)。除多聚化及Tie2參與方面之差異以外,Ang1結合至胞外基質及玻尿酸(內皮糖萼之主要結構組分) (van den Berg BM等人Glomerular Function and Structural Integrity Depend on Hyaluronan Synthesis by Glomerular Endothelium. J Am Soc Nephrol. 2019;30(10):1886-1897)。
天然Ang1主要由血管外被細胞產生。天然Ang1經由其N端結構域及連接子結合胞外基質(ECM),且經由C端Tie2結合類纖維蛋白原結構域(FLD)使相鄰內皮上之Tie2受體活化(Koh GY. Orchestral actions of angiopoietin-1 in vascular regeneration. Trends Mol Med. 2013;19(1):31-39)。此作用模式使得使用天然形式之Ang1達成全身藥物功效具挑戰性。可作為實驗試劑自生物技術供應商獲得之重組Ang1係以三聚、四聚及五聚寡聚物之異質多聚體形式產生(Koh GY. Orchestral actions of angiopoietin-1 in vascular regeneration. Trends Mol Med. 2013;19(1):31-39)。由於其獨特分子結構,SCD-CCOD具有黏性之內在傾向,非特異性地結合至ECM,且形成不溶性聚集體,從而引起沈澱及活性損失(Koh GY. Orchestral actions of angiopoietin-1 in vascular regeneration. Trends Mol Med. 2013;19(1):31-39)。因此,天然Ang1形式不被視為良好之藥物候選物。為避開此等問題,已使用不同設計對若干Ang1模擬物進行生物工程改造以試圖改善溶解度、穩定性及多聚性。一種方法使用以下設計:用來自IgG1之二聚化可結晶片段(Fc)置換SCD-COD以形成具有2之低多聚性的Bow-ANG1 (Davis S等人Angiopoietins have distinct modular domains essential for receptor binding, dimerization and superclustering. Nat Struct Biol. 2003;10(1):38-44)。為了增大多聚性,構築BOW-ANG1之替代型式,其中兩個FLD以串聯排列置於各鏈中以將多聚性加強至4,此顯示對Tie2受體之結合親和力增強(Davis S等人Angiopoietins have distinct modular domains essential for receptor binding, dimerization and superclustering. Nat Struct Biol. 2003;10(1):38-44)。另一方法使用來自與FLD融合之軟骨寡聚基質蛋白之更短且更穩定的CCOD,產生稱為COMP:Ang1之五聚體,其可強烈活化Tie2 (Cho CH等人Designed angiopoietin-1 variant, COMP-Ang1, protects against radiation-induced endothelial cell apoptosis. Proc Natl Acad Sci U S A. 2004;101(15):5553-5558.)。儘管Bow-Ang1及COMP:Ang1在活體內活化Tie2方面確實展示出一些功效,但其缺點(諸如在COMP-Ang1之情況下與胞外基質的非特異性結合及較短血液半衰期,以及BOW-Ang1之低多聚性及較弱效力)使其不適用於臨床試驗(Koh GY. Orchestral actions of angiopoietin-1 in vascular regeneration. Trends Mol Med. 2013;19(1):31-39)。因此,仍需要產生具有改善的溶解度、穩定性及多聚性之Ang1模擬物。
補體結合蛋白(C4BP)為豐富的人類血漿醣蛋白,其天然功能為抑制補體活化之經典及凝集素路徑(Ermert D, Blom AM. C4b-binding protein: The good, the bad and the deadly. Novel functions of an old friend. Immunol Lett. 2016;169:82-92)。在人類血液中之主要形式由七條相同α鏈及單一β鏈構成的情況下,C4BP呈現在C端末端處固持在一起之七臂支架或類章魚結構(Hofmeyer T等人Arranged sevenfold: structural insights into the C-terminal oligomerization domain of human C4b-binding protein. J Mol Biol. 2013;425(8):1302-1317)。此C端核心區負責在蛋白質合成期間裝配成多聚體,其中來自一種單體之半胱胺酸與另一單體之胱胺酸形成分子間二硫鍵(Hofmeyer T等人Arranged sevenfold: structural insights into the C-terminal oligomerization domain of human C4b-binding protein. J Mol Biol. 2013;425(8):1302-1317)。C4BP架構足以寡聚化全長C4BP,具有顯著穩定性,且耐受非常苛刻的條件,諸如暴露於極端pH及溫度(Hofmeyer T等人Arranged sevenfold: structural insights into the C-terminal oligomerization domain of human C4b- binding protein. J Mol Biol. 2013;425(8):1302-1317)。在嵌合融合中,亦預測C4BP能夠寡聚化其他連接結構域,且此處吾等描述C4BP與Ang1之融合(圖1B)。
經由合理設計,本文描述一種血管生成素-1 (ANG1)之新穎「生物較佳」模擬物,其可用作用於經由Tie2活化來治療血管病狀的可注射治療劑。本發明係關於ANG1之C端Tie2結合類纖維蛋白原結構域(FLD)與補體C4結合蛋白(C4BP)之C端架構片段之間的嵌合融合之設計、構築、產生及治療用途。基於其結構域排列之N端至C端次序而稱為ANG1-C4BP或C4BP-ANG1的重組融合經由C4BP片段自然摺疊成七聚結構,且以類似於天然ANG1之組態(圖1A)的「鬱金香花束」類組態呈現ANG1之7個FLD (圖1B)。重組產生之ANG1-C4BP及C4BP-ANG1強效活化人類細胞及小鼠模型中之Tie2。本發明之態樣亦係關於表現此類重組融合蛋白之細胞株,且係關於降低或抑制血管滲漏或血漿滲透性且促進脈管生長並維持脈管之結構完整性的方法。ANG1-C4BP系列生物製劑之治療用途的例示性既定適應症包括血管眼病(諸如由角膜緣毛細管叢或施萊姆氏管(Schlemm's canal)排水系統中之缺陷造成的原發性開角型青光眼)及原發性或繼發性視網膜病變之類型,以及用於如癌症新生血管中之血管滲漏、發炎病狀以及其他適應症的全身性治療。
本文中所提及之專利及科學文獻建立熟習此項技術者可獲得之知識。本文中所引用之所有美國專利及公開或未公開之美國專利申請案均以引用的方式併入。本文中所引用之所有公開的外國專利及專利申請案以引用之方式併入本文中。本文中所引用之所有其他公開的參考文獻、詞典、文獻、手稿、基因體資料庫序列及科學文獻均以引用之方式併入本文中。
本發明之其他特徵及優勢將自圖式及包括實例及申請專利範圍之以下詳細描述顯而易見。
為了使本發明更容易理解,首先在下文定義某些術語。以下術語及其他術語之額外定義闡述於整個本說明書中。
除非上下文另外明確規定,否則如本說明書及隨附申請專利範圍中所使用,單數形式「一(a/an)」及「該(the)」包括複數個指示物。
除非明確陳述或自上下文顯而易見,否則如本文中所使用,術語「或」應理解為包括性的且涵蓋「或」及「及」兩者。
在本文中所使用時,術語「及/或」應視為兩種指定特徵或組分中之每一者具有或不具有另一者之特定揭示內容。因此,諸如本文中之「A及/或B」之片語中所使用的術語「及/或」意欲包括A及B;A或B;A (單獨);及B (單獨)。同樣,諸如「A、B及/或C」之片語中所使用的術語「及/或」意欲涵蓋以下態樣中之每一者:A、B及C;A、B或C;A或C;A或B;B或C;A及C;A及B;B及C;A (單獨);B (單獨);及C (單獨)。
如本文中所使用之術語「例如」及「亦即」僅藉助於實例來使用而不意欲限制,且不應視為僅提及本說明書中明確列舉的彼等條目。
術語「或更大」、「至少」、「超過」及其類似者(例如「至少一個」)應理解為包括(但不限於)至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、144、145、146、147、148、149或150、200、300、400、500、600、700、800、900、1000、2000、3000、4000、5000或超過所陳述值。亦包括任何更大的數目或其間的分數。
相反,術語「不超過」包括小於所陳述值之各值。舉例而言,「不超過100個核苷酸」包括100、99、98、97、96、95、94、93、92、91、90、89、88、87、86、85、84、83、82、81、80、79、78、77、76、75、74、73、72、71、70、69、68、67、66、65、64、63、62、61、60、59、58、57、56、55、54、53、52、51、50、49、48、47、46、45、44、43、42、41、40、39、38、37、36、35、34、33、32、31、30、29、28、27、26、25、24、23、22、21、20、19、18、17、16、15、14、13、12、11、10、9、8、7、6、5、4、3、2、1及0個核苷酸。亦包括任何更小的數目或其間的分數。
術語「複數個」、「至少兩個」、「兩個或更多個」、「至少第二個」及其類似者應理解為包括(但不限於)至少2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95、96、97、98、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126、127、128、129、130、131、132、133、134、135、136、137、138、139、140、141、142、143、144、145、146、147、148、149或150、200、300、400、500、600、700、800、900、1000、2000、3000、4000、5000或更多。亦包括任何更大的數目或其間的分數。
貫穿本說明書,字組「包含(comprising)」或諸如「包含(comprises/comprising)」之變化形式將理解為暗示包括所陳述的要素、整數或步驟,或要素、整數或步驟之群組,但不排除任何其他要素、整數或步驟,或要素、整數或步驟的群組。應理解,每當本文中用語言「包含」描述態樣時,則亦提供以術語「由……組成」及/或「基本上由……組成」描述之類似態樣。
除非特定陳述或自上下文顯而易見,否則如本文中所使用,術語「約」係指在如一般熟習此項技術者所測定之特定值或組成之可接受誤差範圍內的值或組成,此將部分視如何量測或測定該值或該組成(亦即,量測系統之限制)而定。舉例而言,「約」或「基本上包含」可意謂根據此項技術中之實踐在一個或超過一個標準差內。「約」或「基本上包含」可意謂至多10% (亦即,±10%)之範圍。因此,「約」可理解為在大於或小於所陳述值之10%、9%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%、0.1%、0.05%、0.01%或0.001%內。舉例而言,約5 mg可包括4.5 mg與5.5 mg之間的任何量。此外,尤其在生物系統或製程方面,該等術語可意謂一值之至多一個數量級或至多5倍。當特定值或組成提供於本發明中時,除非另外陳述,否則「約」或「基本上包含」之含義應假設為在特定值或組成之可接受誤差範圍內。
「結合親和力」通常係指分子(例如抗體)之單一結合位點與其結合配偶體(例如抗原)之間的非共價相互作用之總和的強度。除非另外指示,否則如本文中所使用,「結合親和力」、「結合至(bind to/binds to)」或「結合至(binding to)」係指反映結合對(例如,抗體Fab片段及抗原)成員之間的1:1相互作用之固有結合親和力。分子X對其配偶體Y之親和力通常可由解離常數(KD)表示。可藉由此項技術中已知之常用方法,包括本文中所描述之彼等方法來量測親和力。低親和力抗體通常緩慢地結合抗原且往往會容易解離,而高親和力抗體通常較快結合抗原且往往會使結合保持更久。量測結合親和力之多種方法為此項技術中已知的,其中之任一者可用於本發明之目的。基於無標記表面電漿子共振(SPR)之生物感測器(諸如BIACORE方法及MM/PBSA方法)及KinExA為通常較佳的標準方法。眾所周知,結合親和力可視分析而改變。因此,出於本發明之目的,當藉由此項技術中之至少一種方法標準來量測時,結合親和力充分地屬於所敍述範圍內。
如本文中所描述,除非另外指示,否則任何濃度範圍、百分比範圍、比率範圍或整數範圍應理解為包括在所敍述範圍內之任何整數值及(在適當時)其分數(諸如整數的十分之一及百分之一)。
使用其國際單位系統(SI)認可的形式來提供本文中所使用之單位、前綴及符號。數值範圍包括界定該範圍之數字。
除非另外定義,否則本文中所使用之所有技術及科學術語均具有與本發明相關之一般熟習此項技術者通常所理解相同的含義。舉例而言,Juo, 「The Concise Dictionary of Biomedicine and Molecular Biology」, 第2版, (2001), CRC Press;「The Dictionary of Cell & Molecular Biology」, 第5版, (2013), Academic Press;及「The Oxford Dictionary Of Biochemistry And Molecular Biology」, Cammack等人編, 第2版, (2006), Oxford University Press,為熟習此項技術者提供本發明中所使用之許多術語的通用辭典。
「投與」係指使用熟習此項技術者已知的各種方法及遞送系統中之任一者將藥劑物理引入至個體中。本說明書之嵌合多肽、核酸及宿主細胞以及其(醫藥)組合物可藉由此項技術中已知的途徑投與有需要之個體,且可視用途,例如待治療之眼部疾病的類型而變化。在一個實施例中,投與為靜脈內注射、腹膜內注射、皮下注射、玻璃體內注射。在一個實施例中,投藥途徑包括例如局部投藥(諸如眼內)及非經腸投藥,諸如皮下、腹膜內、肌肉內、靜脈內、門靜脈內及肝內。在一較佳實施例中,本發明之嵌合多肽、核酸或宿主細胞或其醫藥組合物係藉由局部輸注,例如使用輸注泵及/或導管系統投與個體,達至待治療之位點(諸如實體腫瘤)。在一個實施例中,本說明書之組合物輸注至實體腫瘤、饋入實體腫瘤之血管及/或環繞實體腫瘤之區域中。本文中所揭示之調配物的其他例示性投藥途徑包括靜脈內、肌肉內、皮下、腹膜內、脊髓或其他非經腸投藥途徑,例如藉由注射或輸注。如本文中所使用,片語「非經腸投藥」意謂通常藉由注射進行的除經腸及局部表面(topical)投藥之外的投藥模式,且包括(但不限於)靜脈內、肌肉內、動脈內、鞘內、淋巴管內、病灶內、囊內、眶內、心內、皮內、腹膜內、經氣管、皮下、表皮下、關節內、囊下、蛛膜下、脊髓內、硬膜外及胸骨內注射及輸注,以及活體內電穿孔。在一些實施例中,經由非不經腸(non-parenteral)途徑(例如,經口)投與調配物。其他非不經腸途徑包括局部表面(topical)、表皮或經黏膜投藥途徑,例如鼻內、經陰道、經直腸、舌下或局部表面(topically)。投與亦可執行例如一次、複數次及/或歷經一或多個延長時段。
如本文中所使用,術語「測定」、「評定」、「分析」、「量測」及「偵測」係指定量及定性測定兩者,且因此,術語「測定」在本文中與「分析」、「量測」及其類似者可互換使用。當意欲定量測定時,可使用片語「測定分析物之量」及其類似者。當意欲定性及/或定量測定時,使用片語「測定分析物之含量」或「偵測」分析物。
術語「重組宿主細胞」或「宿主細胞」係指引入有外源性(例如重組) DNA之細胞。此類術語不僅指特定個體細胞,而且指此細胞之後代。因某些修飾可由於突變或環境影響而在後代中出現,故此後代可能實際上與母細胞不一致,但仍包括於如本文中所使用之術語「宿主細胞」之範疇內。在一實施例中,宿主細胞包括原核及真核細胞。在一實施例中,真核細胞包括原生生物、真菌、植物及動物細胞。在另一實施例中,宿主細胞包括(但不限於)原核細胞株大腸桿菌(E. coli);哺乳動物細胞株CHO、HEK 293、COS、NS0、SP2及PER.C6;昆蟲細胞株Sf9;及真菌細胞釀酒酵母(Saccharomyces cerevisiae)。
「載體」係指能夠在生物系統內複製或可在此類系統之間移動的聚核苷酸。載體聚核苷酸通常含有功能在於有助於此等聚核苷酸在諸如細胞、病毒、動物、植物及復原生物系統之生物系統中之複製或維持的元件,諸如複製起點、多腺苷酸化信號或選擇標記物。「表現載體」係指可用於生物系統或復原生物系統中以引導多肽之轉譯的載體,該多肽由表現載體中存在之聚核苷酸序列編碼。
除非另外陳述,否則本文中所揭示之任何範圍意欲涵蓋該範圍之端點。本文中所提供之範圍應理解為對範圍內之所有值的簡寫。舉例而言,1至50之範圍應理解為包括來自由以下組成之群的任何數目、數目之組合或子範圍:1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50。
對「對照」之「參考」意謂比較標準。該標準可為此項技術中之所建立方法。對照參考方法為其中除所測試的變數之外,所有參數均與所比較之方法之彼等參數一致的參考方法。其亦可為由此項技術中通常使用或已知之物量測之參數的平均值。
眾多類型之競爭性結合分析可用於確定一個抗原結合分子是否與另一抗原結合分子競爭,例如:固相直接或間接放射免疫分析(RIA);固相直接或間接酶免疫分析(EIA);夾心競爭分析(Stahli等人, 1983, Methods in Enzymology 9:242-253);固相直接生物素-抗生物素蛋白EIA (Kirkland等人, 1986, J. Immunol. 137:3614-3619);固相直接標記分析、固相直接標記夾心分析(Harlow及Lane, 1988, Antibodies, A Laboratory Manual, Cold Spring Harbor Press);使用1-125標記之固相直接標記RIA (Morel等人, 1988, Molec. Immunol. 25:7-15);固相直接生物素-抗生物素蛋白EIA (Cheung等人, 1990, Virology 176:546-552);及直接標記RIA (Moldenhauer等人, 1990, Scand. J. Immunol. 32:77-82)。
治療劑,例如經工程改造之嵌合多肽的「治療有效量」、「有效劑量」、「有效量」或「治療有效劑量」為當單獨或與另一治療劑組合使用時,保護個體免於疾病發作或促進疾病消退之任何量,該疾病消退係藉由疾病症狀之嚴重程度的降低、無疾病症狀時段之頻率及持續時間的增加或預防由於疾病病痛所引起之損害或障礙來證明。可使用熟習此項技術者已知的多種方法(諸如在臨床試驗期間在人類個體中、在預測在人類中之功效的動物模型系統中),或藉由在活體外分析中分析藥劑之活性來評估治療劑促進疾病消退之能力。視待治療之疾病或病症、待治療之個體的年齡及病狀而定,本發明之分子的劑量可在較寬限值之間變化。
可改變本發明之醫藥組合物中活性成分的實際劑量濃度,以便獲得在對患者無毒之情況下有效達成針對特定患者、投藥模式及組合物之所要治療反應之活性成分的量。所選劑量濃度將視包括以下之多種藥代動力學因素而定:所採用的本發明之特定組合物的活性、投藥途徑;投藥時間;所採用之特定化合物之排泄速率;治療持續時間;與所採用之特定組合物組合使用的其他藥物、化合物及/或材料;所治療之患者之年齡、性別、體重、病狀、一般健康狀況及先前醫療史;及醫學技術中熟知之類似因素。一般熟習此項技術之醫師或獸醫可容易確定及開具所需醫藥組合物之有效量。舉例而言,醫師或獸醫可以低於為了達成所要治療效果所需之含量的醫藥組合物中所採用之本發明化合物的劑量開始,且逐漸增加劑量直至達成所要效果。一般而言,本發明之組合物之適合日劑量將為有效產生治療效果之最低劑量的化合物之量。此有效劑量通常將視上文所描述之因素而定。可藉由此項技術中已知之醫療裝置投與組合物。非限制性實施例包括針頭、無針皮下注射裝置、用於連續藥物遞送之可變流量植入式輸注設備、具有多腔室隔室之滲透藥物遞送系統。
視需要,治療組合物之有效日劑量可視情況以單位劑型在當天以適當時間間隔分別投與之兩次、三次、四次、五次、六次或更多次子劑量進行投與。雖然本發明之化合物有可能單獨投與,但該化合物較佳以醫藥調配物(組合物)形式進行投與。
術語「核酸」、「核酸序列」、「核苷酸序列」或「聚核苷酸序列」及「聚核苷酸」可互換使用。其係指任何長度之核苷酸(去氧核糖核苷酸或核糖核苷酸)的聚合形式或其類似物。聚核苷酸可為單股或雙股的,且若為單股,則可為編碼股或非編碼(反義)股。聚核苷酸可包含經修飾之核苷酸,諸如甲基化核苷酸及核苷酸類似物。核苷酸之序列可間雜有非核苷酸組分。可在聚合之後,諸如藉由與標記組分結合而進一步修飾聚核苷酸。核酸可為重組聚核苷酸,或基因體、cDNA、半合成或合成來源之聚核苷酸,其不存在於自然界中或以非天然排列連接至另一聚核苷酸。cDNA為合成聚核苷酸之一典型實例。
術語「肽」、「多肽」及「蛋白質」可互換使用,且係指包含藉由肽鍵共價連接之胺基酸殘基的化合物。蛋白質或肽含有至少兩個胺基酸,且對可包含蛋白質或肽之序列的最大胺基酸數目沒有限制。多肽包括包含兩個或更多個藉由肽鍵彼此接合之胺基酸的任何肽或蛋白質。如本文中所使用,該術語係指短鏈(其在此項技術中通常亦稱為例如肽、寡肽及寡聚物)及長鏈(其在此項技術中通常稱為蛋白質,其存在許多類型)。「多肽」包括例如生物活性片段、實質上同源多肽、寡肽、均二聚體、異二聚體、多肽之變異體、經修飾多肽、衍生物、類似物、融合蛋白以及其他物質。多肽包括天然肽、重組肽、合成肽或其組合。
術語「減少」及「降低」在本文中可互換使用,且指示小於原始之任何變化。「減少」及「降低」為需要在量測前與量測後之間進行比較的相對術語。「減少」及「降低」包括完全耗盡。
個體之「治療(treatment/treating)」係指以逆轉、減輕、緩解、抑制、減緩或預防症狀、併發症或病狀的發作、進展、發展、嚴重程度或復發或與疾病相關之生物化學標誌為目標,對個體執行之任何類型之干預或方法或向個體投與活性劑。在一個實施例中,術語「治療(treat/treatment/treating)」係指因投與一或多種療法而減少或減輕病症(例如增生性病症)之進展、嚴重程度及/或持續時間,或減輕病症之一或多種症狀(較佳地,一或多種可辨別症狀)。在一些實施例中,其中經改善之一或多種症狀係選自由以下組成之群:無力、疲乏、呼吸短促、容易瘀傷及出血、頻繁感染、淋巴結增大、腹部擴張或疼痛、骨骼或關節疼痛、骨折、非計劃性體重減輕、食慾不振、盜汗、持續性輕度發熱及排尿減少。在特定實施例中,術語「治療」係指減輕患者未必可辨別的增生性病症之至少一個可量測生理參數,諸如腫瘤生長。在其他實施例中,術語「治療」係指在物理上藉由例如穩定可辨別症狀、在生理學上藉由例如穩定生理參數或兩者來抑制增生性病症之進展。
如本文中所使用之術語「個體」包括人類及非人類動物。非人類動物包括所有脊椎動物,例如哺乳動物及非哺乳動物,諸如非人類靈長類動物、綿羊、狗、貓、奶牛、雞、兩棲動物及爬行動物。
為計算一致性百分比,通常以給出序列之間的最大匹配之方式來比對所比較之序列。可用於測定一致性百分比之電腦程式的一個實例為GCG程式包,其包括GAP (Devereux等人, 1984, Nucl. Acid Res. 12:387;Genetics Computer Group, University of Wisconsin, Madison, Wis.)。電腦演算法GAP用於比對序列一致性百分比待測定之兩個多肽或聚核苷酸。序列經比對以用於其各別胺基酸或核苷酸之最佳匹配(「匹配跨度」,如由演算法所測定)。在某些實施例中,演算法亦使用標準比較矩陣(對於PAM 250比較矩陣,參見Dayhoff等人, 1978, Atlas of Protein Sequence and Structure 5:345-352;對於BLOSUM 62比較矩陣,參見Henikoff等人, 1992, Proc. Natl. Acad. Sci. U.S.A. 89:10915-10919)。
嵌合多肽
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融合蛋白
ANG1-C4BP及C4BP-ANG1分別係指在任一方向上呈N端至C端次序之ANG1 C端FLD與C4BP端片段之間的嵌合融合。一般而言,ANG1-C4BP變異體係指ANG1-C4BP及C4BP-ANG1之兩種結構域排列類型,且亦包括具有不同的連接子排列及標籤位置之融合的所有形式。
在一個實施例中,本發明係關於血管生成素-1之C端Tie2結合類纖維蛋白原結構域(FLD)與C4BP之C端架構片段之間的嵌合融合之設計、構築、產生及治療用途。本發明提供一種血管生成素-1 (ANG1)之新模擬物,其可用於經由Tie2活化來治療血管病狀。在一個實施例中,本發明提供一種迄今尚未研究之策略,其藉由用C4BP血漿蛋白之片段置換ANG1之SCD-CCOD以便獲得在循環系統中自由循環的能力。在一些實施例中,嵌合融合蛋白為「生物較佳的」ANG1。
在一個實施例中,本發明提供重組融合(基於其結構域排列之N端至C端次序而稱為ANG1-C4BP或C4BP-ANG1)經由C4BP片段自然摺疊成七聚結構,且以類似於天然ANG1之組態(圖1A)的「鬱金香花束」類組態呈現ANG1之7個FLD (圖1B)。
在一個實施例中,人類血清C4BP α鏈之C端架構片段與人類ANG1 FLD之連接子融合為C4BP-ANG1或ANG1-C4BP。在一個實施例中,在具有ANG1之嵌合融合蛋白中,C4BP片段形成錨定多聚C4BP裝配體且摺疊成呈現七個ANG1頭基(七價)之穩定七聚中心莖結構(圖1)的封閉環結構。藉由經由鏈間二硫鍵結合之七聚多聚化的設計特徵,嵌合融合蛋白中之七個ANG1 FLD形成同源Tie2受體之高親合力配位體,從而引起Tie2之強效結合及促效活化。
在一個實施例中,ANG1與C4BP之間的重組融合可包括額外純化標籤序列(諸如6xHis標籤),且具有或不具有用於標籤移除之內肽酶裂解序列。
在一些實施例中,重組ANG1-C4BP融合包括具有ANG1與C4BP片段之間的替代性結構域排列及在此等片段當中之排列的變異體以及額外純化標籤及內肽酶裂解序列。
在一個實施例中,C4BP蛋白包含NCBI寄存編號NP_000706.1中所提供之序列。在一個實施例中,血管生成素1蛋白包含NCBI寄存編號NP_001137.2中所提供之序列。
在一個實施例中,本發明提供一種多肽,其選自以下多肽及其功能片段或衍生物中之任一者。
在一個實施例中,本發明提供一種多肽,其包含與上述序列中之任一者具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致性的序列。在一個實施例中,多肽與本文中所描述之ANG1-C4BP或C4BP-ANG1中之至少一者競爭以在活體外及/或活體內結合至Tie2。在一個實施例中,多肽以約100 μM或更小、約50 μM或更小、約25 μM或更小或約10 μM或更小的親和力結合Tie-2;更佳地具有約1 μM或更小、約100 nM或更小、約50 nM或更小、約25 nM或更小的高親和力;較佳在約1 nM至約10 nM;約10 nM至約20 nM;約20 nM至約30 nM;約30 nM至約40 nM;約40 nM至約50 nM;約50 nM至約60 nM;約60 nM至約70 nM;約70 nM至約80 nM;約80 nM至約90 nM;或約90 nM至約100 nM之範圍內的結合親和力。
在一個實施例中,多肽用於偵測。在一個實施例中,多肽結合至標記。在一個實施例中,標記為放射活性標記或螢光標記。
核酸、載體及細胞
在一個實施例中,本發明提供編碼本發明之多肽之核酸。在一個實施例中,核酸包含以下序列中之一或多者:
在一個實施例中,本發明提供一種核酸,其包含與上述序列中之任一者具有至少90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%一致性的序列。在一個實施例中,核酸序列經密碼子最佳化。
在一個實施例中,本發明提供一種載體,其包含本發明之核酸序列中之一或多者。某些載體能夠在其所引入之宿主細胞中自主複製(例如,具有細菌複製起點之細菌載體及游離型哺乳動物載體)。其他載體(例如非游離型哺乳動物載體)可在引入宿主細胞中時整合至宿主細胞之基因體中,且藉此與宿主基因體一起複製。某些載體能夠引導其可操作地連接之基因的表現。此類載體在本文中稱為「重組表現載體」(或簡稱為「表現載體」)。一般而言,在重組DNA技術中有用的表現載體通常呈質體形式。在本發明書中,由於質體為最常用形式之載體,因而「質體」與「載體」可互換使用。然而,亦包括提供等效功能之其他形式的表現載體,諸如病毒載體(例如,慢病毒、反轉錄病毒、複製缺陷反轉錄病毒、腺病毒及腺相關病毒、疱疹病毒)。術語「慢病毒」係指反轉錄病毒科之屬。慢病毒因其能夠感染非分裂細胞而在反轉錄病毒當中為獨特的;其可將大量遺傳資訊遞送至宿主細胞之DNA中,因此其為基因遞送載體之最有效方法中之一者。在一些實施例中,慢病毒載體為人類免疫缺乏病毒1 (HIV-1);人類免疫缺乏病毒2 (HIV-2);維斯納-梅迪病毒(visna-maedi virus;VMV)病毒;山羊關節炎-腦炎病毒(CAEV);馬感染性貧血病毒(EIAV);貓免疫缺乏病毒(FIV);牛免疫缺乏病毒(BIV);或猿猴免疫缺乏病毒(SIV)載體。基因修飾細胞以表現本發明之spFv分子的其他手段包括轉位酶、mRNA轉染、非整合性慢病毒、「睡美人(Sleeping Beauty;SB)」轉座子、核酸內切酶、用DNA奈米載體進行原位轉染。
在一些實施例中,載體為腺病毒載體、腺病毒相關載體、DNA載體、慢病毒載體、質體、反轉錄病毒載體或RNA載體。在一些實施例中,載體為病毒載體。在一些實施例中,載體為反轉錄病毒載體。在一些實施例中,載體為慢病毒載體。
在一個實施例中,本發明提供一種宿主細胞,其包含本發明之多肽。在一個實施例中,本發明提供一種宿主細胞,其包含本發明之核酸。
在一個實施例中,本發明提供一種宿主細胞,其包含本發明之載體。在本說明書中之別處提供宿主細胞之實例。
組合物
在一個態樣中,本發明提供一種組合物,其包含本文中所揭示之多肽。在一個態樣中,本發明提供一種本文中所描述之核酸。在一個態樣中,本發明提供一種組合物,其包含所描述之載體。在一個態樣中,本發明提供一種組合物,其包含本文中所描述之宿主細胞。
在一個實施例中,組合物為醫藥組合物,其包含本文中所描述之聚核苷酸、本文中所描述之載體、本文中所描述之多肽或本文中所描述之宿主細胞。在一些實施例中,組合物包含醫藥學上可接受之載劑、稀釋劑、增溶劑、乳化劑、防腐劑及/或佐劑。
在一特定實施例中,術語「醫藥學上可接受」意謂經聯邦政府或洲政府之監管機構批准,或在美國藥典或其他一般公認的藥典中列出用於動物,且更特定言之用於人類。術語「載劑」係指與治療劑一起投與之稀釋劑、佐劑、賦形劑或媒劑。此類醫藥載劑可為無菌液體,諸如水及油,包括石油、動物、植物或合成來源之彼等油,諸如花生油、大豆油、礦物油、芝麻油及其類似者。當靜脈內投與醫藥組合物時,水為較佳載劑。生理鹽水溶液及右旋糖水溶液以及甘油溶液亦可用作液體載劑,特定言之用於可注射溶液之液體載劑。適合的醫藥賦形劑包括澱粉、葡萄糖、乳糖、蔗糖、明膠、麥芽、大米、麵粉、白堊、矽膠、硬脂酸鈉、甘油單硬脂酸酯、滑石、氯化鈉、磷酸鈉、乙酸鈉、L-組胺酸、脫脂牛奶、甘油、丙烯、二醇、水、乙醇及其類似者。視需要,組合物亦可含有少量潤濕劑或乳化劑或pH緩衝劑。此等組合物可呈溶液、懸浮液、乳液、錠劑、丸劑、膠囊、散劑、持續釋放調配物及其類似者之形式。一般而言,本發明之組合物的成分分開供應或以單位劑型混合在一起,例如對於基於載體及多肽之組合物,呈在氣密密封式容器(諸如指示活性劑之量的安瓿或藥囊)中之乾燥凍乾粉末或無水濃縮物形式。當藉由輸注投與組合物(例如,宿主細胞組合物)時,可省去含有無菌醫藥級水或生理鹽水之輸注瓶。當藉由注射投與組合物時,可提供注射用無菌水或生理鹽水之安瓿,使得可在投與之前混合該等成分。
本發明之組合物包括適用於製造醫藥組合物(例如,不純或非無菌組合物)之散裝藥物組合物,及可用於製備單位劑型之醫藥組合物(亦即,適用於投與個體或患者之組合物)。此類組合物包含防治有效量或治療有效量的本文中所揭示之防治性及/或治療性雙特異性多肽分子(藥劑)或藥劑與醫藥學上可接受之載劑的組合。較佳地,本發明之組合物包含防治有效量或治療有效量的本發明之一或多種分子及醫藥學上可接受之載劑。醫藥組合物較佳包含呈游離形式或呈鹽形式之分子。較佳地,鹽為分子之醫藥學上可接受之鹽,諸如氯化物或乙酸(三氟乙酸)鹽。必須注意,由於分子在活體內不為鹽,因而根據本發明之分子的鹽實質上不同於其活體內狀態下之分子。在一態樣中,水性載劑含有多個組分,諸如水以及非水載劑組分,諸如本文中所描述之彼等組分。在另一態樣中,當與本文中所描述之肽或其他分子組合時,水性載劑能夠賦予改良的特性,例如改良的溶解度、功效及/或改良的免疫療法。另外,組合物可含有賦形劑,諸如緩衝劑、結合劑、噴射劑(blasting agent)、稀釋劑、調味劑、潤滑劑等。舉例而言,「醫藥學上可接受之稀釋劑」可包括生理學上相容的溶劑、填充劑、穩定劑、分散介質、包衣、抗細菌劑及抗真菌劑、等張劑及吸收延遲劑以及其類似者。醫藥學上可接受之稀釋劑的實例包括生理鹽水、磷酸鹽緩衝鹽水、右旋糖、甘油、乙醇及其類似者中之一或多者以及其組合。在許多情況下,在組合物中將較佳包括一或多種等張劑,例如糖(諸如海藻糖及蔗糖)、多元醇(諸如甘露糖醇、山梨糖醇)或氯化鈉。醫藥學上可接受之物質,諸如潤濕劑或少量輔助物質,諸如潤濕劑或乳化劑、防腐劑或緩衝劑亦在本發明之範疇內。另外,組合物可含有賦形劑,諸如緩衝劑、結合劑、噴射劑、稀釋劑、調味劑及潤滑劑。
在一態樣中,本文中所描述之肽或其他分子可與水性載劑組合。在一態樣中,水性載劑係選自離子交換劑;礬土;硬脂酸鋁;硬脂酸鎂;卵磷脂;血清蛋白,諸如人類血清白蛋白;緩衝物質,諸如磷酸鹽、甘胺酸、山梨酸、山梨酸鉀、飽和植物脂肪酸之偏甘油酯混合物;鹽或電解質,諸如硫酸魚精蛋白、磷酸氫二鈉、磷酸二鈣、磷酸氫鉀、氯化鈉、鋅鹽、膠體二氧化矽、三矽酸鎂、聚乙烯吡咯啶酮、聚乙烯吡咯啶酮-乙酸乙烯酯;基於纖維素之物質(例如,微晶纖維素、羥丙基甲基纖維素、乙酸羥丙基甲基纖維素丁二酸酯、羥丙基甲基纖維素鄰苯二甲酸酯);澱粉;單水合乳糖;甘露糖醇;海藻糖月桂基硫酸鈉;及交聯羧甲基纖維素鈉;聚乙二醇;羧甲基纖維素鈉;聚丙烯酸酯;聚甲基丙烯酸酯;蠟;聚乙烯-聚氧化丙烯嵌段聚合物;及羊毛脂。
在其他實施例中,組合物經選擇以用於非經腸遞送、吸入或經由消化道(諸如經口)遞送。此類醫藥學上可接受之組合物的製備在熟習此項技術者之能力內。在某些實施例中,緩衝劑用於將組合物維持在生理pH或略低的pH,通常在約5至約8之pH範圍內。在某些實施例中,當考慮非經腸投與時,組合物在醫藥學上可接受之媒劑中呈包含本文中所描述之組合物、具有或不具有額外治療劑的無熱原非經腸可接受之水溶液形式。在某些實施例中,用於非經腸注射之媒劑為無菌蒸餾水,其中具有或不具有至少一種額外治療劑的本文中所描述之組合物調配為適當防腐之無菌等張溶液。在某些實施例中,製備涉及用聚合化合物(諸如聚乳酸或聚乙醇酸)、珠粒或脂質體調配所要分子,該等聚合化合物、珠粒或脂質體提供產物之控制或持續釋放,隨後經由儲槽式注射進行遞送。在某些實施例中,植入式藥物遞送裝置用於引入所要分子。
組合物之pH通常不應等於本發明之特定嵌合多肽的等電點,且可介於約4.0至約7.0、約5.0至約6.0或約5.5至約6.0之範圍內。在某些實施例中,本發明之組合物或調配物具有約5.5、5.6、5.7、5.8、5.9或6.0之pH。緩衝劑可有助於將本發明之組合物的pH維持在接近生理條件之範圍內。其可以約2 mM至約50 mM之範圍內的濃度存在。用於本發明之適合緩衝劑包括有機酸及無機酸兩者以及其鹽,諸如檸檬酸鹽緩衝劑(例如,檸檬酸單鈉-檸檬酸二鈉混合物、檸檬酸-檸檬酸三鈉混合物、檸檬酸-檸檬酸單鈉混合物等)、丁二酸鹽緩衝劑(例如,丁二酸-丁二酸單鈉混合物、丁二酸-氫氧化鈉混合物、丁二酸-丁二酸二鈉混合物等)、酒石酸鹽緩衝劑(例如,酒石酸-酒石酸鈉混合物、酒石酸-酒石酸鉀混合物、酒石酸-氫氧化鈉混合物等)、反丁烯二酸鹽緩衝劑(例如,反丁烯二酸-反丁烯二酸單鈉混合物、反丁烯二酸-反丁烯二酸二鈉混合物、反丁烯二酸單鈉-反丁烯二酸二鈉混合物等)、葡糖酸鹽緩衝劑(例如,葡糖酸-葡糖酸鈉混合物、葡糖酸-氫氧化鈉混合物、葡糖酸-葡糖酸鉀混合物等)、草酸鹽緩衝液(例如,草酸-草酸鈉混合物、草酸-氫氧化鈉混合物、草酸-草酸鉀混合物等)、乳酸鹽緩衝劑(例如,乳酸-乳酸鈉混合物、乳酸-氫氧化鈉混合物、乳酸-乳酸鉀混合物等)及乙酸鹽緩衝劑(例如,乙酸-乙酸鈉混合物、乙酸-氫氧化鈉混合物等)。另外,可使用磷酸鹽緩衝劑、組胺酸緩衝劑及三甲胺鹽,諸如Tris。
可添加防腐劑以延緩微生物生長,且可以0.2%至1% (w/v)之範圍內的量添加防腐劑。用於本發明之適合防腐劑包括苯酚、苯甲醇、間甲酚、對羥基苯甲酸甲酯、對羥基苯甲酸丙酯、氯化十八烷基二甲基苯甲基銨、苄烷銨鹵化物(例如,氯化物、溴化物及碘化物)、氯化六羥季銨及對羥基苯甲酸烷基酯,諸如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯、鄰苯二酚、間苯二酚、環己醇及3-戊醇。有時稱為「穩定劑」之等張劑可經添加以確保本發明之液體組合物的等張性,且包括多羥基糖醇,例如三元醇或更高級糖醇,諸如甘油、赤藻糖醇、阿拉伯糖醇、木糖醇、山梨糖醇及甘露糖醇。穩定劑係指廣泛類別之賦形劑,其功能可介於填充劑至使治療劑溶解或有助於防止變性或黏附至容器壁之添加劑的範圍內。典型穩定劑可為多羥基糖醇(上文所列舉);胺基酸,諸如精胺酸、離胺酸、甘胺酸、麩醯胺酸、天冬醯胺、組胺酸、丙胺酸、鳥胺酸、L-白胺酸、2-苯丙胺酸、麩胺酸、蘇胺酸等;有機糖或糖醇,諸如乳糖、海藻糖、水蘇糖、甘露糖醇、山梨糖醇、木糖醇、核糖醇、肌肉肌醇、半乳糖醇、甘油及其類似者,包括環醇,諸如肌醇;聚乙二醇;胺基酸聚合物;含硫還原劑,諸如脲、麩胱甘肽、硫辛酸、硫代乙酸鈉、硫甘油、α-單硫甘油及硫代硫酸鈉;低分子量多肽(例如,具有10個殘基或更少之肽);蛋白質,諸如人類血清白蛋白、牛血清白蛋白、明膠或免疫球蛋白;親水聚合物,諸如聚乙烯吡咯啶酮單醣,諸如木糖、甘露糖、果糖、葡萄糖;雙醣,諸如乳糖、麥芽糖、蔗糖;及三醣,諸如棉子糖;以及多醣,諸如聚葡萄糖。穩定劑可以每重量份活性蛋白0.1重量至10,000重量之範圍存在。
可添加非離子性界面活性劑或清潔劑(亦稱為「潤濕劑」)以有助於溶解治療劑以及保護含Ang1分子免於攪動誘導性聚集,此亦准許調配物暴露於受應力之剪切表面而不引起蛋白質變性。適合的非離子性界面活性劑包括聚山梨醇酯(20、80及其他)、聚氧雜劑(polyoxamer) (184、188及其他)、普洛尼克多元醇(Pluronic polyol)、聚氧乙烯脫水山梨糖醇單醚(TWEEN-20、TWEEN-80及其他)。非離子性界面活性劑可以約0.05 mg/mL至約1.0 mg/mL之範圍,例如約0.07 mg/mL至約0.2 mg/mL之範圍存在。
亦提供用於工程改造、製備及產生細胞之方法、含有該等細胞之組合物以及含有且用於使用、產生及投與該等細胞的套組及裝置。本文中所描述之組合物中之任一者可包含於套組中。套組組分提供於適合的容器構件中。
使用方法
在一個實施例中,本發明提供重組產生之ANG1-C4BP及C4BP-ANG1在人類細胞及/或小鼠模型中活體外、活體內強效活化Tie2。
在一個實施例中,本發明提供減少或抑制血管滲漏或血漿滲透性之方法。在一個實施例中,本發明提供促進脈管之生長且維持脈管之內皮結構完整性的方法。
在一個實施例中,ANG1-C4BP系列生物製劑之治療用途的例示性既定適應症包括血管眼病(諸如由角膜緣毛細管叢或施萊姆氏管排水系統中之缺陷造成的原發性開角型青光眼)及原發性或繼發性視網膜病變之類型,以及用於如癌症新生血管中之血管滲漏、發炎病狀以及其他適應症的全身性治療。在一些實施例中,由於本發明的嵌合多肽之未預期有利特性,本發明之嵌合多肽比迄今描述之任何其他血管生成素相關之生物製劑(包括Bow-Ang1及COMP:Ang1)更具生物學活性。
在一個實施例中,本發明提供一種降低有需要之個體中之血管滲透性或滲漏的方法,其包含向該個體投與有效量的本發明之多肽、本發明之細胞、本發明之核酸、本發明之載體、本發明之蛋白質複合物及/或本發明之醫藥組合物。在一個實施例中,皮膚、眼、肺、腎、腦、肝、心臟及腸中之血管滲透性或滲漏已增加。在一個實施例中,血管滲透性或滲漏已因回應於選自以下物質上升的含量而增加:VEGF、包括毒性氣體之化學劑、感染性細菌及病毒、自體免疫性抗體以及引起內皮功能障礙及血管損壞之抗體藥物。
在一個實施例中,本發明提供一種治療有需要之個體的伴有異常血管滲透性或滲漏之疾病或病症的方法,其包含向個體投與有效量的本發明之多肽、本發明之細胞、本發明之核酸、本發明之載體、本發明之蛋白質複合物及/或本發明之醫藥組合物。
在一個實施例中,本發明提供一種治療有需要之個體的對Tie2活化起反應之疾病或病症之方法,其包含向個體投與有效量的本發明之多肽、本發明之細胞、本發明之核酸、本發明之載體、本發明之蛋白質複合物及/或本發明之醫藥組合物。在一個實施例中,對Tie2活化起反應之疾病或病症為任何疾病或病症,其中症狀之至少一種病徵或嚴重程度、患者經歷此症狀之頻率或兩者係藉由Tie2活化來減少或消除。
在一個實施例中,病症係選自腫瘤血管生成中之癌症及癌轉移、眼部疾病或病症(諸如青光眼)、細菌性敗血症、重度病毒感染、原蟲感染(諸如惡性瘧原蟲瘧疾)、發炎、致死性炭疽病、慢性腎病、急性腎損傷及腎功能障礙、急性肺損傷及支氣管功能障礙、急性呼吸窘迫症候群、阻塞性肺病、急性肝衰竭、急性胰臟炎、中風、心肌梗塞、充血性心臟衰竭、肌肉萎縮性側索硬化症、阿茲海默氏病(Alzheimer's disease)、杭丁頓氏病(Huntington's disease)、帕金森氏病(Parkinson's disease)、外周神經病變、糖尿病性腎病變及視網膜病變、傷口癒合、關節炎、纖維變性病狀、缺血-再灌注損傷、創傷性腦損傷、癲癇症、多發性硬化症、器官移植及同種異體移植排斥反應。
在一個實施例中,癌症係選自以下中之任一者:急性淋巴球性癌、急性骨髓白血病、齒槽橫紋肌肉瘤、骨癌、腦癌、乳癌、肛門癌、肛管癌或肛腸癌、眼癌、肝內膽管癌、關節癌、頸癌、膽囊癌或胸膜癌、鼻癌、鼻腔癌或中耳癌、口腔癌、陰道癌、外陰癌、慢性淋巴球性白血病、慢性骨髓癌、結腸癌、食道癌、子宮頸癌、胃腸道類癌、神經膠質瘤、霍奇金淋巴瘤(Hodgkin lymphoma)、喉咽癌、腎癌、喉癌、肝癌、肺癌、惡性間皮瘤、黑色素瘤、多發性骨髓瘤、鼻咽癌、非霍奇金淋巴瘤、口咽癌、卵巢癌、陰莖癌、胰臟癌、腹膜癌、腸網膜癌及腸系膜癌、咽癌、前列腺癌、直腸癌、腎癌、皮膚癌、小腸癌、軟組織癌、胃癌、睪丸癌、甲狀腺癌、子宮癌、尿管癌以及膀胱癌。在一個實施例中,用本發明化合物治療係與包括(但不限於)化學療法及放射線之其他癌症療法組合。
在一個實施例中,本發明係關於一種治療有需要之個體之血管生成介導之疾病的方法。方法包含投與有效量的包括上文所描述之任何其他藥劑的組合物。能夠得到治療之例示性血管生成介導之疾病包括非眼部出血、心肌梗塞、中風、癌症、動脈粥樣硬化、缺血性心臟病、冠心病、周邊動脈疾病、傷口癒合病症及其類似者。
在一個實施例中,眼部疾病或病症係選自由以下組成之群:老年性黃斑部病變(AMD)、黃斑部病變、黃斑部水腫、糖尿病性黃斑部水腫(DME) (包括局灶性非中心DME及瀰漫性中心性DME)、視網膜病變、糖尿病性視網膜病變(DR) (包括增生性DR (PDR)、非增生性DR (NPDR)及高山性DR)、其他缺血相關之視網膜病變、早產兒視網膜病變(ROP)、視網膜靜脈栓塞(RVO) (包括中央(CRVO)及分支(BRVO)形式)、CNV (包括近視CNV)、角膜新生血管、與角膜新生血管相關之疾病、視網膜新生血管、與視網膜/脈絡膜新生血管相關之疾病、病理性近視、逢希伯-林道病(von Hippel-Lindau disease)、眼組織漿菌病、家族性滲出性玻璃體視網膜病變(FEVR)、寇氏病(Coats' disease)、諾里病(Norrie disease)、骨質疏鬆假神經膠質瘤症候群(Osteoporosis-Pseudoglioma Syndrome;OPPG)、結膜下出血、虹膜紅變、眼部新生血管性疾病、新生血管性青光眼、色素性視網膜炎(RP)、高血壓視網膜病變、視網膜血管瘤增生、黃斑部毛細管擴張、虹膜新生血管、眼內新生血管、視網膜變性、囊樣黃斑部水腫(CME)、脈管炎、視神經乳頭水腫、視網膜炎、結膜炎(包括感染性結膜炎及非感染性(例如過敏性)結膜炎)、雷伯氏先天性黑蒙(Leber congenital amaurosis)、葡萄膜炎(包括感染性及非感染性葡萄膜炎)、脈絡膜炎、眼部組織漿菌病、瞼炎、乾眼、創傷性眼損傷及薛格連氏病(Sjögren's disease)。在一個實施例中,眼部疾病或病症為青光眼、AMD或DME。
在一個實施例中,本發明提供一種增強經由有需要之個體的眼中之習知流出道之水狀液流出的方法,其包含向個體投與有效量的本發明之多肽、本發明之細胞、本發明之核酸、本發明之載體、本發明之蛋白質複合物及/或本發明之醫藥組合物,藉此增強經由個體之眼中之習知流出道的水狀液流出。
一種降低有需要之個體之眼內壓的方法,其包含向個體投與有效量的本發明之多肽、本發明之細胞、本發明之核酸、本發明之載體、本發明之蛋白質複合物及/或本發明之醫藥組合物,藉此降低個體之眼內壓。
在一個實施例中,方法進一步包含投與第二藥劑。在一個實施例中,第二藥劑係選自抗體、抗炎劑、抗血管生成劑、細胞介素、細胞介素拮抗劑、皮質類固醇及鎮痛劑。
在一個實施例中,抗血管生成劑包括選自以下之化合物:VE-PTP抑制劑、貝伐單抗(bevacizumab)、伊曲康唑(itraconazole)、羧胺三唑、TNP-470、CM101、INF-α、IL-12、血小板因子-4、蘇拉明(suramin)、SU5416、凝血酶致敏蛋白、VEGFR拮抗劑、血管生成抑制性類固醇加肝素、軟骨源血管生成抑制因子、基質金屬蛋白酶抑制劑、血管生長抑素、內皮生長抑素、2-甲氧雌二醇、替康蘭(tecogalan)、四硫鉬酸鹽、沙立度胺(thalidomide)、催乳素、利諾胺(linomide)、ανβ3抑制劑、雷莫蘆單抗(ramucirumab)、他喹莫德(tasquinimod)、雷珠單抗(ranibizumab)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、帕唑帕尼(pazopanib)及依維莫司(everolimus)。
在一個實施例中,抗血管生成劑為VEGF拮抗劑。在一個實施例中,VEGF拮抗劑為抗VEGF抗體、抗VEGF受體抗體、可溶性VEGF受體融合蛋白、適體(例如哌加他尼(pegaptanib) (MACUGEN®))、抗VEGF DARPin® (例如培戈阿比西帕(abicipar pegol))或VEGFR酪胺酸激酶抑制劑(例如,4-(4-溴-2-氟苯胺基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(ZD6474)、4-(4-氟-2-甲基吲哚-5-基氧基)-6-甲氧基-7-(3-吡咯啶-1-基丙氧基)喹唑啉(AZD2171)、凡塔藍尼(vatalanib) (PTK787)、西瑪米尼(semaxaminib) (SU5416)及SUTENT® (舒尼替尼)。在一個實施例中,抗VEGF抗體為雷珠單抗(LUCENTIS®)、RTH-258或雙特異性抗VEGF抗體。在一個實施例中,雙特異性抗VEGF抗體為抗VEGF/抗Ang2抗體。在一個實施例中,抗VEGF/抗Ang2抗體為RG-7716。在一個實施例中,可溶性VEGF受體融合蛋白為阿柏西普(aflibercept) (EYLEA®)。
適用於與本文中所揭示之組合物及方法組合的額外治療劑包括(但不限於)依魯替尼(ibrutinib) (IMBRUVICA®)、奧伐木單抗(ofatumumab) (ARZERRA®)、利妥昔單抗(rituximab) (RITUXAN®)、貝伐單抗(AVASTIN®)、曲妥珠單抗(trastuzumab) (HERCEPTIN®)、曲妥珠單抗恩他新(trastuzumab emtansine) (KADCYLA®)、伊馬替尼(imatinib) (GLEEVEC®)、西妥昔單抗(cetuximab) (ERBITUX®)、帕尼單抗(panitumumab) (VECTIBIX®)、卡妥索單抗(catumaxomab)、替伊莫單抗(ibritumomab)、奧伐木單抗、托西莫單抗(tositumomab)、本妥昔單抗(brentuximab)、阿侖珠單抗(alemtuzumab)、吉妥珠單抗(gemtuzumab)、埃羅替尼(erlotinib)、吉非替尼(gefitinib)、凡德他尼(vandetanib)、阿法替尼(afatinib)、拉帕替尼(lapatinib)、奈拉替尼(neratinib)、阿西替尼(axitinib)、馬賽替尼(masitinib)、帕唑帕尼、舒尼替尼、索拉非尼、妥賽蘭尼(toceranib)、來妥替尼(lestaurtinib)、西地尼布(cediranib)、樂伐替尼(lenvatinib)、尼達尼布(nintedanib)、瑞戈非尼(regorafenib)、司馬沙尼(semaxanib)、替沃紮尼(tivozanib)、恩曲替尼(entrectinib)、卡博替尼(cabozantinib)、伊馬替尼、達沙替尼(dasatinib)、尼羅替尼(nilotinib)、普納替尼(ponatinib)、拉多替尼(radotinib)、伯舒替尼(bosutinib)、盧可替尼(ruxolitinib)、帕瑞替尼(pacritinib)、考比替尼(cobimetinib)、司美替尼(selumetinib)、曲美替尼(trametinib)、貝美替尼(binimetinib)、艾樂替尼(alectinib)、色瑞替尼(ceritinib)、克唑替尼(crizotinib)、阿柏西普、脂肪肽、地尼白介素(denileukin diftitox)、mTOR抑制劑(諸如依維莫司及替西羅莫司(Temsirolimus))、刺蝟抑制劑(諸如索尼德吉(sonidegib)及維莫德吉(vismodegib))以及CDK抑制劑(諸如CDK抑制劑(帕泊昔布(palbociclib)))。
抗炎劑或藥物包括(但不限於)類固醇及糖皮質激素(包括倍他米松(betamethasone)、布地奈德(budesonide)、地塞米松(dexamethasone)、乙酸氫化可體松(hydrocortisone acetate)、氫化可體松、甲基普賴蘇穠(methylprednisolone)、普賴蘇穠(prednisolone)、普賴松(prednisone)、曲安西龍(triamcinolone))、非類固醇抗炎藥物(NSAIDS),包括阿司匹靈(aspirin)、布洛芬(ibuprofen)、萘普生(naproxen)、甲胺喋呤、柳氮磺胺吡啶(sulfasalazine)、來氟米特(leflunomide)、抗TNF藥品、環磷醯胺及黴酚酸酯(mycophenolate)。例示性NSAID包括布洛芬、萘普生、萘普生鈉、Cox-2抑制劑及唾液酸化物(sialylate)。例示性鎮痛劑包括乙醯胺苯酚(acetaminophen)、羥考酮(oxycodone)、鹽酸丙氧芬(proporxyphene hydrochloride)之曲馬多(tramadol)。例示性糖皮質激素包括可體松(cortisone)、地塞米松、氫化可體松、甲基普賴蘇穠、普賴蘇穠或普賴松。例示性生物反應調節劑包括針對細胞表面標記物之分子(例如CD4、CD5等)、細胞介素抑制劑,諸如TNF拮抗劑(例如,依那西普(etanercept) (ENBREL®)、阿達木單抗(adalimumab) (HUMIRA®)及英利昔單抗(infliximab) (REMICADE®)、趨化因子抑制劑及黏附分子抑制劑。生物反應調節劑包括單株抗體以及重組形式之分子。例示性DMARD包括硫唑嘌呤(azathioprine)、環磷醯胺、環孢靈(cyclosporine)、甲胺喋呤、青黴胺(penicillamine)、來氟米特、柳氮磺胺吡啶、羥基氯奎(hydroxychloroquine)、金製劑(經口(金諾芬(auranofin))及肌肉內)及二甲胺四環素(minocycline)。
方法可包括以下之其他步驟:測定ANG1-C4BP及其變異體在動物模型中之功效;及評估Tie2之全身性活化(諸如在肺中),藉此測定生物製劑之功效。用於該等方法中之動物可為嚙齒動物或更大的動物,諸如兔。然而,任何適當動物均可充當活體內動物模型。Tie2相關疾病或病症之活體內動物模型為此項技術中熟知的。
實例
實例1:構築體設計及小規模表現
編碼ANG1-C4BP嵌合融合構築體(圖2)之cDNA的基因合成係在GenScript®公司執行。將構築體之密碼子最佳化(CHO密碼子偏置) cDNA次選殖至pTT81®表現載體或類似者中,且短暫轉染CHO及HEK293細胞以供小規模生產分析(圖3)。使用短暫表現,測試融合至C4BP之ANG1及ANG2之不同嵌合構築體。所有重組融合蛋白均分泌為約280 kDa之七聚體,其中構築體H6EKC4BPAng1及H6EKAng1C4BP以最高水準表現,如在非還原性及還原性條件下之Ponceau S溶液染色(圖3A)以及使用抗His-Tag抗體之非還原性及還原性SDS-PAGE西方墨點(圖3B)所展示。藉由在存在及不存在還原劑β-巰基乙醇之情況下比較蛋白質在SDS-PAGE凝膠上之行為來證實重組融合蛋白的多聚狀態。
實例2:血管生成素 -C4BP 及 C4BP- 血管生成素之大規模表現
對於不同ANG1-C4BP構築體之穩定表現,藉由添加甲硫胺酸磺基肟(MSX)持續大約兩週來轉染及選擇加拿大國家研究委員會(Canada's National Research Council,NRC) CHO-BRI (純系55E1)細胞。追蹤穩定CHO-BRI之彙集表現及振盪器燒瓶中之分批進料生產。在維持於所要溫度下的具有5% CO2
覆層之含濕氣培育箱中在定軌振盪器上攪動培養物。使細胞維持於化學成分確定之PowerCHO2培養基中,同時使用BalanCD生長A作為補充有MSX及0.3%普洛尼克F68之基礎培養基來執行分批進料培養。對於分批進料培養,每天調整進料速率以維持培養物中之所規定恆定葡萄糖含量。CHO-BRI為重組蛋白產生之穩定表現系統,其使用cumate可誘導表現平台以產生CHO池,該等CHO池在轉染後四週(兩週用於池選擇及擴增,且兩週用於生產)內穩定表現在200 mg/L與1000 mg/L之間(Poulain A等人Rapid protein production from stable CHO cell pools using plasmid vector and the cumate gene-switch. J Biotechnol. 2017;255:16-27)。
在用SDS-PAGE考馬斯藍染色(圖4)以及非還原性(圖5)及還原性(圖6) SDS-PAGE分離及藉由抗His-Tag抗體之免疫墨點法分析之後,發現嵌合融合血管生成素-C4BP構築體之重組蛋白產物處於預期分子量。因此,ANG1-C4BP及C4BP-ANG1嵌合融合蛋白之穩定CHO表現展示在細胞培養基中自組裝為所預測七聚體。
執行振盪器燒瓶中之分批進料生產以獲得重組蛋白,將該等重組蛋白採集且藉由離心及過濾,隨後使用溶離之梯度進行固定化金屬親和層析(IMAC)純化,去鹽且緩衝液更換為DPBS,濃縮,無菌過濾來純化,並且藉由在280 nm下之吸光度定量。藉由UPLC-SEC (超效能液相層析-尺寸排阻層析)進一步分析所純化材料以測定聚集含量,且藉由SDS-PAGE (還原性與非還原性)來進行純度測定。在2號峰溶離份中發現重組融合蛋白產物處於正確分子量(圖7A)。概述關於所產生之各重組融合蛋白之體積及總量的峰1及2之IMAC純化溶離份(圖7B)。
經純化ANG1-C4BP經歷-80℃下之冷凍儲存以及至多兩輪冷凍及解凍(F/T)循環,以測定蛋白穩定性(圖8)。在此等條件下,未觀測到可辨UPLC-SEC分析特徵變化,從而表明穩定性。
實例3:ANG1-C4BP 及 C4BP-ANG1 之活體外生物活性
測試經純化之ANG1-C4BP及C4BP-ANG1與同Fc重組融合之Tie2 (稱為Tie2-Fc)之胞外域的功能性結合。ANG1-C4BP及C4BP-ANG1兩者均可結合Tie2-Fc (圖9)。
為測定ANG1-C4BP之效力,在處理20分鐘之HUVEC中量測半數最大有效濃度(EC50
)。ANG1-C4BP之磷酸化AKT (pAKT) EC50
為87 ng/mL (圖10)。
為評定生物活性及效力,使用自嵌合融合構築體獲得之不同重組蛋白產物以將各種濃度下之HUVEC處理20分鐘。ANG1與C4BP之間的嵌合融合構築體之重組蛋白產物有效活化(磷酸化) Tie2受體酪胺酸激酶(圖11A),且誘導其下游目標AKT之磷酸化(圖11B)。唯一例外為由融合至血管生成素-2 FLD之C4BP製成之嵌合構築體的產物(C4bpAng2H6)。在細胞水準下,C4BP-ANG1刺激Tie2,且在所培養HUVEC中重組其亞細胞分佈。在C4BP-ANG1處理之後,細胞表面Tie2叢集化且彙集至接合點(圖12)。總而言之,呈任一組態之ANG1-C4BP及C4BP-ANG1重組融合蛋白形成穩定七聚體,該等七聚體結合至同源Tie2受體,從而使得其活化與ANG1-C4BP變異體之預期七價叢集化效果一致。
實例4:C4BP-ANG1 之活體內生物活性
為測定C4BP-ANG1之活體內生物活性,以0.2微克/公克體重至1微克/公克體重之範圍內的不同濃度對BALB/c小鼠進行靜脈內注射(圖13A)。所使用之三種濃度使得肺中之Tie2以劑量依賴性方式活化。C4BP-ANG1在15分鐘內活化Tie2 (圖13B)且在處理後持續至少6小時,其中較低程度活化在處理後16小時時較明顯(圖13C)。
在眼部藥代動力學實驗中使用三種白色新西蘭兔,以測定在單次玻璃體內注射重組融合蛋白之後的水狀液中C4BP-ANG1的含量。在將100 μg之C4BP-ANG1玻璃體內注射至各兔右眼中之前,且自注射後第1天直至第7天藉由執行每日水狀液輕觸收集來收集水狀液。在第7天使兔安樂死之後收集玻璃狀液。兔中之玻璃體內注射展示水狀液(AH)中之持續性C4BP-ANG1持續數天,如藉由ELISA所量測,以前兩天至前三天中之峰值開始且隨後逐漸調平至基線(圖14)。將需要具有較大敏感性之方法以在玻璃體內注射之後三天偵測C4BP-ANG1的AH含量。甚至在處理後七天之後,在來自右眼之玻璃狀液(VH)中偵測到C4BP-ANG1,而左側VH充當媒劑陰性對照(圖14)。
為測定C4BP-ANG1之活體內功效,在BALB/c小鼠中使用伊凡氏藍染料(邁爾斯分析)進行四種不同的血管滲透性研究。伊凡氏藍染料對血清白蛋白具有極高親和力,且其在間質空間中之存在指示蛋白質之血液血管滲漏。在VEGF誘導之皮下滲透性邁爾斯分析中,C4BP-ANG1顯著減少血管滲漏(圖15)。將VEGF及C4BP-ANG1單獨或一起皮下注射於小鼠中,且藉由量測在630 nm下之光學密度來定量伊凡氏藍染料(圖15)。替代局部皮下注射C4BP-ANG1,在皮下VEGF之前30分鐘靜脈內注射生物製劑亦展示藉由C4BP-ANG1處理之血管滲漏減少(圖16)。類似地,全身性靜脈內注射C4BP-ANG1亦降低化學誘導性血管滲漏之嚴重程度(圖17)。在肺部血管滲透性分析中,靜脈內注射C4BP-ANG1減輕經歷細菌脂多醣(LPS)吸入以誘導肺中之血管滲漏的小鼠中之血管滲漏(圖18)。總伊凡氏藍染料萃取及量測展示用C4BP-ANG1處理之小鼠中之滲漏減少(圖18)。總體而言,此等活體內結果表明C4BP-ANG1之穩固生物活性及其血管保護作用。
實例5:血管生成素模擬物之 C4BP-ANG1 遞送的具有活體內生物活性之青光眼模型活化 SC 中之 內源性 TEK 信號傳導 , 且藉由增強房水流暢係數 (outflow facility) 來降低 IOP , 以及改良 TM-SC 結構及功能且保護嚙齒動物青光眼模型中之 RGC
眼內壓升高(IOP)為青光眼之發展及進展的主要風險因素,且由對水狀液流出之阻力增加造成。IOP降低展現出降低在具有眼部高壓之眼中轉化為青光眼的風險,且降低在具有現存青光眼損傷之眼中疾病惡化的風險。先前已展示,受損之血管生成素/Tie2信號傳導使施萊姆氏管完整性受損且誘導青光眼。
雖然特別期望旨在恢復增加流出阻力之患病組織之功能的療法,但當前存在極少此類療法。此等患病組織駐留於包含近小管組織、小樑網(TM)及施萊姆氏管(SC)之習知流出道中。(Stamer, W.D.等人, Biomechanics of Schlemm's canal endothelium and intraocular pressure reduction. Progress in Retinal & Eye Research, 2015. 44:第86-98頁。)血管生成素(Angpt)-TEK血管信號傳導路徑之活性降低導致小鼠中之嚴重形式的原發性先天性青光眼(PCG),且在患有PCG之孩童之TEK基因中存在已知突變。血管酪胺酸激酶受體TEK (表現於SC內皮中)藉由其配位體血管生成素(由TM表現)之活化係SC發育所需的,該SC為眼睛之角膜緣區中之指定圓形血管(其為水狀液流出及IOP維持所必需的)。小鼠中SC缺陷之嚴重程度、眼部高壓及視網膜神經節細胞(RGC)損失與Angpt/TEK信號傳導之活性成反比,且提昇TEK活性可降低IOP並且防止RGC死亡。TEK基因或編碼其配位體ANGPT1之基因中的功能突變缺失導致PCG (20名患者中鑑別出20種獨特突變)。ANGPT1基因體區域中之變異體與成年人中之原發性開角型青光眼(POAG)相關且據報導,Angpt/TEK信號傳導減少導致成年猴中之青光眼。
C4BP-ANG1
蛋白係使用CellFactoryTM系統產生,且藉由FPLC純化。玻璃體內注射展示AH中之由ELISA量測的持續性Angpt1高達6小時。基於注射至玻璃體中之其他蛋白的藥代動力學,預測眼睛及前房中之持久表現。
C4BP-ANG1
之活體內活性展示於三種具有眼部病症之小鼠模型中:
a. Prox1+-GFP血壓正常小鼠[Truong, T.N.等人, Novel characterization and live imaging of Schlemm's canal expressing Prox-1. 2014. 9(5): p. e98245] (在C57Bl6背景上具有螢光SC之Prox1-GFP)
b. TEK+/-小鼠(伴有RGC細胞損失緩慢之輕度低形態SC管);對照為經媒劑處理之眼睛
c. NC-Angpt1 KO (重度低形態SC,PCG模型);對照為經媒劑處理之眼睛
歸因於C4-ANPGT1蛋白之大小,其不會穿透成熟血液-視網膜障壁,且因此其係藉由玻璃體內注射遞送。來自具有螢光 SC 之 對照小鼠的血壓正常眼中之房水流暢係數、 IOP
血壓正常眼之小鼠模型用以確定C4BP-ANG1
是否可降低IOP且增強血壓正常眼中之房水流暢係數,以及TEK在SC中保持活化多長時間。在Prox1啟動子下表現增強的綠色螢光蛋白(GFP)之3個月齡B57Bl6小鼠[Truong, T.N.等人, Novel characterization and live imaging of Schlemm's canal expressing Prox-1. 2014.9(5): p. e98245]使得容易鑑別SC;使用回彈眼壓量測法量測IOP;量測對房水流暢係數之影響[Sherwood, J.M.等人, Measurement of Outflow Facility Using iPerfusion. 2016. 11(3): p. e0150694];藉由SC之免疫組織化學使用磷酸特異性TEK抗體來測定TEK活化[Kim, J.等人, Impaired angiopoietin/Tie2 signaling compromises Schlemm's canal integrity and induces glaucoma. Journal of Clinical Investigation, 2017. 127(10):第3877- 3896頁];以確定是否出現全身性藥物吸收,採集肺及對側對照眼,且在此等組織中藉由西方墨點及免疫染色測定TEK活化。
時間點:向3個月齡WT小鼠之群組玻璃體內注射1 μl的1 μg/ul經純化之C4BP-ANG1
蛋白、媒劑(1微克/微升白蛋白),或用0.01%拉坦前列素(latanoprost)作為陽性對照進行局部表面(topically)處理。在注射後2小時、6小時、24小時及1週時測定Tie2/TEK之定位及磷酸染色。在解剖之前立即量測房水流暢係數。在第二組動物中,在基線、處理後1 h、2 h、4 h、8小時及24小時量測IOP。執行量測重複三次。在1週群組中,採集SC及TM且如先前所描述進行組織學分析[Thomson, B.R.等人, Angiopoietin-1 is required for Schlemm's canal development in mice and humans. Journal of Clinical Investigation, 2017. 127(12):第4421-4436頁]。青光眼模型之 ANGPT1 模擬物治療 (TEK+/1 , NC‐Angpt1) :
小鼠模型用以確定是否存在SC及流出道之任何結構或功能救援,且在上文所列之2種青光眼模型(一個輕度及一個重度)中之任一者中是否防止進展性RGC損失。測試兩個時間點:1)在通常出現活性SC生長時之早期產後時段及2)已經具有升高的IOP及RGC損失但尚未達到末期之年齡為6週齡的小鼠。
早期時段:在產後第3天(P3)及P5給予兩次注射,且在P7採集眼睛。讀數與上文所描述之彼等讀數類似。如先前所描述進行SC形態、免疫染色、大小及回旋定量,TM組織學分析[Thomson, B.R.等人, Angiopoietin-1 is required for Schlemm's canal development in mice and humans. Journal of Clinical Investigation, 2017. 127(12):第4421-4436頁;Thomson, B.R., Carota, I.A., Souma, T., Soman, S., Vestweber, D., Quaggin, S.E., Targeting the vascularspecific phosphatase PTPRB protects against retinal ganglion cell loss in a pre-clinical model of glaucoma. eLife, 2019]。鑒於難以量測流出或量測此等年輕小鼠中之IOP,主要讀數為此早期時間點處之結構救援。基於Angpt-VEGF肽體注射在停止SC生長之小鼠中的類似給藥排程來選擇時間點[Thackaberry, E.A.等人, Rapid Development of Glaucoma Via ITV Nonselective ANGPT 1/2 Antibody: A Potential Role for ANGPT/TIE2 Signaling in Primate Aqueous Humor Outflow. 2019. 60(13):第4097-4108頁]。
患有青光眼之年輕成年小鼠,6週:首先尋求來自對照小鼠中之詳細藥代動力學資料的結果以確定注射之最佳時間間隔及劑量。選擇在經證實以增強定量於西方墨點上之TEK磷酸化的濃度下使得Angpt1含量最低點為約50%之注射劑量的時間間隔給藥。讀數包括採集時間處之SC免疫染色、大小、回旋、形態及TM組織學(12週齡)。藉由在基線及每週進行回彈眼壓量測法來量測IOP。
實例6C4BP-ANG1 之活體內生物活性 施萊姆氏管大小之救援
用C4BP-ANG1藉由自產後第0至4天每日腹膜內注射來處理野生型及神經脊特異性血管生成素-1基因敲除(Angpt1 dNC)小鼠。在P14,收集眼睛且定量施萊姆氏管面積。在野生型眼及Angpt1 dNC眼兩者中,C4BP-Ang1處理引起施萊姆氏管大小顯著增加。在WT動物中,在處理之後維持分化施萊姆氏管標記物PROX1之表現,而在Angpt1 dNC眼中,僅在C4BP-Ang1處理之後觀測到PROX1表現。圖19。
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圖1展示七聚C4BP-ANG1的示意圖及實際形成。A)天然ANG1自N端至C端次序包含超叢集結構域(SCD)、捲曲螺旋結構域(CCOD)及結合Tie2之類纖維蛋白原結構域(頂部)。CCOD介導ANG1分子(中間)之間的CCOD-CCOD相互作用,且經由其與FLD之連接片段亦結合ECM。SCD進一步將ANG1叢集化為較高程度的複合物(底部)。B) C4BP之C端經由相鄰亞單元之間的連接間二硫橋鍵(紅色)而自然摺疊成「筒狀」結構。總共七個(或八個)此等亞單元完成筒狀結構(頂部),在C4BP-ANG1或ANG1-C4BP中,該筒狀結構顯示七個呈使人聯想到天然ANG1 (底部,與A相比)的排列形式之FLD。C) C4BP-ANG1經由將編碼質體轉染至HEK-293細胞中得以表現,且自培養基將其收集。如所預期,C4BP-ANG1在非還原性(NR)條件下在SDS PAGE上形成七聚體。D)電子顯微圖(EM)影像展示叢集化C4BP-ANG1。
圖2 (A至G)為HEK293及CHO細胞中產生及表現之血管生成素及C4BP嵌合融合構築體之不同型式的概述。
圖3展示在培養基中CHO及HEK293對ANG1-C4BP七聚體的表現。各種血管生成素-C4bp融合構築體在CHO及HEK293 (所測試之三種轉染條件1至3)細胞兩者中之短暫表現。構築體H6EKC4BPAng1及H6EKAng1C4BP以最高水準表現,其中在如A)在非還原性及還原性條件下之Ponceau S溶液染色及B)使用抗His-Tag抗體之非還原性及還原性SDS PAGE西方墨點所展示的還原性條件下,正確形成約280 kDa七聚體(上圖)及約35 kDa單體(下圖)。
圖4展示C4BP及ANG1融合變異體全部形成近似均質性之七聚體(部分1)。在N端至C端次序中,構築用於哺乳動物細胞表現之4種質體:1.具有C端6xHis標籤之C4BP-ANG1(1)、2.具有N端6xHis標籤的C4BP-ANG(2)、3.具有C端6xHis標籤之ANG1-C4BP(1)及4.具有N端6xHis標籤的ANG1-C4BP(2)。使蛋白質在培養於無血清培養基中之CHO細胞中表現,且隨後自培養基採集該等蛋白質。藉由在非還原性(N.R.:左圖)或還原性(右圖)條件下執行SDS PAGE分析,確定不管其N至C次序如何,C4BP-ANG1蛋白(以紅色框突出顯示)經由二硫橋鍵自然形成約280 kDa之七聚體(具有7之多重性)。所有融合蛋白均可在還原性條件下還原為其約35 kDa之單體形式。
圖5展示形成七聚體的經純化ANG1-C4BP變異體(部分2)。在非還原性SDS PAGE分離及使用抗His-Tag抗體之西方墨點分析之後,發現嵌合融合蛋白之產物在所有構築體中處於預期分子量。#2表示使用C4BPAng1H6之替代性表現載體以供比較。CHO-BRI穩定彙集表現平台技術用以產生此等ANG-C4BP變異體。
圖6展示形成七聚體的經純化ANG1-C4BP變異體(部分3)。在非還原性SDS-PAGE分離及使用抗His-Tag抗體之西方墨點分析之後,發現嵌合融合蛋白之產物在所有構築體中處於預期分子量。#2表示使用C4BPANG1H6之替代性表現載體以供比較。CHO-BRI穩定彙集表現平台技術用以產生此等ANG-C4BP變異體。
圖7展示含有ANG1-C4BP變異體之七聚體的2號峰之IMAC純化。A)經IMAC純化之片段的非還原性及還原性SDS PAGE考馬斯藍(Coomassie blue)染色。2號峰具有在非還原性條件下之重組融合蛋白產物-七聚體形成及在還原性條件下之單體形成的正確分子量。B)對經IMAC純化之片段的概述,突出顯示2號峰。
圖8展示在冷凍-解凍循環之後的ANG1-C4BP嵌合融合蛋白穩定性。在對七聚體品質(在峰2.610處)進行UPLC-SEC分析之前,使經純化ANG1-C4BP經歷一個或兩個冷凍-解凍循環(F/T)。無七聚體片段之損失為顯而易見的(比較1 F/T及2 F/T與在4℃下儲存之對照組)。
圖9展示ANG1-C4BP及C4BP-ANG1與Tie2的結合。以Fc融合(Tie2-Fc)之形式使用Tie2的胞外域,在共免疫沈澱分析中測試天然ANG1序列、ANG1-C4BP或C4BP-ANG1之Tie2與重組ANG1 (rANG1)之間的直接相互作用。在抗Fc免疫沈澱之後,藉由抗His標籤墨點法偵測ANG1變異體之存在。免疫墨點影像係來自用抗His及抗Fc抗體進行雙重染色之複合物。
圖10展示ANG1-C4BP在所培養HUVEC中以劑量依賴性方式活化Tie2。在用ANG1-C4BP之預製備SEC2號峰處理20分鐘之後,在HUVEC中觀測到AKT磷酸化量(pAKT)增加。Ang1-C4bp在處理20分鐘之HUVEC中活化pAKT時的半數最大反應(EC50
)為87 ng/mL。
圖11展示ANG1-C4BP變異體以劑量依賴性方式活化Tie2。ANG1與C4BP之間的嵌合融合為活體外Tie2受體之強效促效劑,如藉由A) Tie2之磷酸化增加及B)其下游目標AKT所證明。在HUVEC中執行該實驗,其中在處理20分鐘時各重組嵌合融合蛋白具有所指示或500 ng/mL之濃度。rhAngpt1為來自R&D系統之重組血管生成素-1。
圖12展示C4BP-ANG1誘導Tie2再局域化至細胞外周中之基因座。HUVEC細胞為經FLAG-Tie2 (全長)轉染且經歷媒劑對照或C4BP-ANG1處理之轉基因。自抗FLAG免疫螢光染色顯影綠色之Tie2影像(展示來自各組之代表性單一細胞影像)。
圖13展示C4BP-ANG1之靜脈內及腹膜內注射活化小鼠中之內源性Tie2。向小鼠注射C4BP-ANG1,且藉由肺中之內源性Tie2 (pTyr-Tie2)的磷酸化來量測活體內活性。A)基於體重(BW)向小鼠靜脈內注射不同劑量的媒劑或C4BP-ANG1,且在30分鐘之後採集肺組織。在抗Tie2免疫沈澱之後,藉由使用抗pTyr抗體之免疫墨點法量測磷酸化Tie2含量。B)及C)展示回應於0.5 μg/g.BW之C4BP-ANG1之磷酸化Tie2的時程研究。
圖14展示兔眼中經玻璃體內注射之C4BP-ANG1的藥代動力學。三隻兔各自經歷單次劑量之C4BP-ANG1玻璃體內注射,且每日(注射前樣本:第0天)收集水狀液持續七天。藉由ELISA使用抗His捕捉抗體及抗ANG1偵測抗體(OD450值)量測C4BP-ANG1之含量(左)。在第七天,處死動物且收集玻璃狀液樣本以偵測C4BP-ANG1含量(右,星號:p<0.01)。
圖15展示C4BP-ANG1在邁爾斯分析(Miles assay)中減少小鼠中之VEGF誘導性血管滲漏。使用定量伊凡氏藍染料(Evans Blue dye)之組織含量的邁爾斯分析來進行血管滲漏之研究。小鼠經歷如所展示之30 min注射排程(頂部)。進行VEGF與C4BP-ANG1之組合的皮下(SQ)注射,且觀察到伊凡氏藍之滲漏(底部)並且將其定量為藉由組織重量標準化的OD360值(影像及定量,右方星號:p<0.001)。
圖16展示C4BP-ANG1之靜脈內注射減少VEGF誘導性血管滲漏。使用定量伊凡氏藍染料之組織含量的邁爾斯分析來進行血管滲漏之研究。小鼠經歷如所展示之30 min注射排程(頂部)。替代C4BP-ANG1之局部(local)注射,在藉由皮下(SQ)注射VEGF進行滲漏誘導之前60分鐘,經由靜脈內以防治性方式投與生物製劑。觀察到伊凡氏藍之滲漏(底部)。
圖17展示C4BP-ANG1之靜脈內注射減少化學誘導性血管滲漏。使用定量伊凡氏藍染料之組織含量的邁爾斯分析來進行血管滲漏之研究。在藉由向耳部局部表面(topical)施用氮芥油進行滲漏誘導之前60分鐘,經由靜脈內以防治性方式投與C4BP-ANG1之注射劑(影像及定量,星號:p<0.01)。
圖18展示C4BP-ANG1避免小鼠中之脂多醣誘導性肺損傷。在脂多醣(LPS)誘導性肺損傷之小鼠模型中,LPS吸入(INH)、C4BP-ANG1注射及伊凡氏藍注射之時程遵循頂部圖中所指示來進行。在伊凡氏藍注射之後一小時,採集肺以量測血管滲漏(影像及定量,星號:p<0.05)。
圖19野生型及神經脊特異性血管生成素-1基因剔除(Angpt1 dNC)小鼠用Angpt1-C4PB藉由自產後第0至14天每日腹膜內注射進行處理。在P14,收集眼睛且定量施萊姆氏管面積。在野生型眼及Angpt1 dNC眼兩者中,Angpt1-C4BP處理引起施萊姆氏管大小顯著增加。在WT動物中,在處理之後維持分化施萊姆氏管標記物PROX1之表現,而在Angpt1 dNC眼中,僅在Angpt1-C4BP處理之後觀測到PROX1表現。
圖20展示無標籤Ang1C4bp構築體的表現、純化以及活體外及活體內Tie2活化。表現構築體含有訊息肽,隨後為Ang1 FLD、「GGGS」連接子及呈N端至C端次序之C4bp序列。使用CHO細胞系統,無標籤Ang1-連接子-C4bp融合經表現且分泌至培養基中。A)在離子交換層析之後,自管柱溶離出蛋白質峰(左)。對收集物之非還原性SDS PAGE分析展示目標無標籤蛋白質Ang1C4bp濃縮於溶離份F4及F5中(右圖:以紅框突出顯示,且大小藉由紅色箭頭指示)。B)將溶離份F4與F5合併且裝載至尺寸排阻層析管柱上以對目標蛋白進行「拋光」,此引起進一步富集(左圖:層析圖追蹤展示目標蛋白,由紅色箭頭指示;右圖:SDS PAGE證實目標蛋白成功富集於溶離份F2中,由紅色箭頭指示)。C)分別在經活化之胞內Akt磷酸化(pAkt)及Tie2磷酸化(pTie2)中處理具有無標籤Ang1C4bp之HUVEC及HEK293細胞(穩定表現Tie2-FLAG轉基因)。媒劑對照(Ctr)及天然Ang1分別用作陰性及陽性對照。D)向小鼠靜脈內注射無標籤Ang1C4bp重組蛋白以誘導肺中之Tie2磷酸化。在注射後1小時,採集來自媒劑注射(Ctr: n=3)及來自無標籤Ang1C4bp注射(n=3)之肺組織。使總Tie2自肺組織均質物(抗Tie2 IP)免疫沈澱(IP),且藉由用抗磷酸酪胺酸抗體(pTie2)對IP樣本進行免疫墨點法來測定Tie2磷酸化量。
Claims (54)
- 一種嵌合多肽,其包含補體蛋白C4結合蛋白(C4bp)之C端結構域與血管生成素(Ang)之類纖維蛋白原結構域(FLD)。
- 如請求項1之嵌合多肽,其中該C4bp結構域在該多肽之N端處,且該Ang結構域在該多肽之C端處,藉此形成C4bp-Ang多肽。
- 如請求項1之嵌合多肽,其中該Ang結構域在該多肽之該N端處,且該C4bp結構域在該多肽之該C端處,藉此形成Ang-C4bp多肽。
- 如請求項1至3中任一項之嵌合多肽,其中該Ang為Ang1或Ang2。
- 如請求項1至4中任一項之嵌合多肽,其中C4bp之該C端結構域包含SEQ ID NO.:1。
- 如請求項1至5中任一項之嵌合多肽,其中Ang1之該類纖維蛋白原結構域包含SEQ ID NO.:2,且Ang2之該類纖維蛋白原結構域包含SEQ ID NO.:3。
- 如請求項1至6中任一項之嵌合多肽,其中Ang1-C4bp包含SEQ ID NO.:8,C4bp-Ang1多肽包含SEQ ID NO.:10;且C4bp-Ang2包含SEQ ID NO.:12、其少HIS標籤型式、及其含訊息肽型式。
- 如請求項1至7中任一項之嵌合多肽,其中該多肽進一步包含訊息肽。
- 如請求項8之嵌合多肽,其中該訊息肽係選自IL2之訊息肽及人類CD33之訊息肽。
- 如請求項1至9中任一項之嵌合多肽,其中該多肽包含具有或不具有C端標記/標籤之訊息肽。
- 如請求項1至9中任一項之嵌合多肽,其中該多肽進一步包含該C4bp結構域與該Ang結構域之間的連接肽。
- 如請求項1至11中任一項之嵌合多肽,其中該連接肽係選自包含胺基酸序列GGGGS、EAAAK、PAPAP、AEAAAKEAAAKA、KESGSVSSEQLAQFRSLD及EGKSSGSGSESKST之連接子。
- 如請求項1至12中任一項之嵌合多肽,其中該多肽包含無C端標記之連接子。
- 如請求項1至13中任一項之嵌合多肽,其中該多肽進一步包含N端及/或C端標記。
- 如請求項1至14中任一項之嵌合多肽,其中該標記係選自poly-His、GST、MBP、Flag、CBP及蛋白A標記/標籤。
- 如請求項1至15中任一項之嵌合多肽,其中該多肽包含SEQ ID NO.: 9、10、11、12、13或18。
- 如請求項1至16中任一項之嵌合多肽,其進一步包含腸激酶裂解位點。
- 如請求項1至15中任一項之嵌合多肽,其中該多肽包含SEQ ID NO.: 15、16或17。
- 如請求項1至18中任一項之嵌合多肽,其中利用至少一種本發明之標準分析,該多肽在活體外及/或活體內結合至Tie2,及/或活化Tie2,及/或活化AKT之磷酸化。
- 如請求項1至19中任一項之嵌合多肽,其中該多肽降低血管滲透性。
- 如請求項20之嵌合多肽,其中該多肽降低皮膚、眼及/或肺中之血管滲透性。
- 如請求項20之嵌合多肽,其中該多肽減少由VEGF、諸如LPS之細菌代謝物、諸如芥子油之化學毒素或其他感染及化學毒性引起之血管滲透性的增加。
- 一種核酸,其編碼如請求項1至22中任一項之多肽。
- 如請求項23之核酸,其中核酸序列經密碼子最佳化以在細菌、酵母或哺乳動物細胞中表現該多肽。
- 如請求項23至24中任一項之核酸,其中該核酸包含SEQ ID NO.: 19至24。
- 一種重組載體,其包含如請求項23至25中任一項之核酸。
- 如請求項26之重組載體,其中該載體為腺病毒載體、反轉錄病毒載體、慢病毒載體等。
- 一種蛋白質複合物,其包含七種嵌合多肽,其中該等多肽係選自如請求項1至22中任一項之多肽。
- 一種細胞,其包含如請求項1至22中任一項之多肽、如請求項23至25中任一項之核酸、如請求項26及27中任一項之載體、及/或如請求項28之蛋白質複合物。
- 一種醫藥組合物,其包含如請求項23至25中任一項之核酸、如請求項26及27中任一項之載體、如請求項28之蛋白質複合物、及/或如請求項29之細胞,及醫藥學上可接受的載劑、賦形劑或稀釋劑。
- 一種降低有需要之個體中之血管滲透性或滲漏的方法,其包含向該個體投與有效量的如請求項1至22中任一項之多肽、如請求項29之細胞、如請求項23至25中任一項之核酸、如請求項26及27中任一項之載體、如請求項28之蛋白質複合物、及/或如請求項30之醫藥組合物。
- 如請求項30之方法,其中皮膚、眼、肺、腎、腦、肝、心臟及/或腸中之該血管滲透性或滲漏已增加。
- 如請求項31之方法,其中該血管滲透性或滲漏已因回應於選自VEGF、感染媒介物、毒性化學品等物質上升的含量而增加。
- 一種治療有需要之個體的伴有異常血管滲透性或滲漏之疾病或病症的方法,其包含向該個體投與有效量的如請求項1至22中任一項之多肽、如請求項29之細胞、如請求項23至25中任一項之核酸、如請求項26及27中任一項之載體、及/或如請求項28之蛋白質複合物。
- 一種治療有需要之個體的對Tie2活化起反應之疾病或病症或與病理性血管生成相關之疾病或病症的方法,其包含向該個體投與有效量的如請求項1至22中任一項之多肽、如請求項29之細胞、如請求項23至25中任一項之核酸、如請求項26及27中任一項之載體、如請求項28之蛋白質複合物、及/或如請求項30之醫藥組合物,藉此活化Tie2。
- 如請求項34之方法,其中對Tie2活化起反應之疾病或病症為任何疾病或病症,其中症狀之至少一種病徵或嚴重程度、患者經歷此症狀之頻率或兩者係藉由Tie2活化來減少或消除。
- 如請求項33至36中任一項之方法,其中該病症係選自癌症、眼部疾病或病症、敗血症、發炎、腎功能障礙、中風、心肌梗塞、充血性心臟衰竭、肌肉萎縮性側索硬化症、阿茲海默氏病(Alzheimer's disease)、杭丁頓氏病(Huntington's disease)、帕金森氏病(Parkinson's disease)、外周神經病變、創傷性腦損傷、癲癇症及多發性硬化症(在合理之情況下列出其他病症)。
- 如請求項37之方法,其中該眼部疾病或病症係選自由以下組成之群:老年性黃斑部病變(AMD)、黃斑部病變、黃斑部水腫、糖尿病性黃斑部水腫(DME) (包括局灶性非中心DME及瀰漫性中心性DME)、視網膜病變、糖尿病性視網膜病變(DR) (包括增生性DR (PDR)、非增生性DR (NPDR)及高山性DR)、其他缺血相關之視網膜病變、早產兒視網膜病變(ROP)、視網膜靜脈栓塞(RVO) (包括中央(CRVO)及分支(BRVO)形式)、CNV (包括近視CNV)、角膜新生血管、與角膜新生血管相關之疾病、視網膜新生血管、與視網膜/脈絡膜新生血管相關之疾病、病理性近視、逢希伯-林道病(von Hippel-Lindau disease)、眼組織漿菌病、家族性滲出性玻璃體視網膜病變(FEVR)、寇氏病(Coats' disease)、諾里病(Norrie Disease)、骨質疏鬆假神經膠質瘤症候群(Osteoporosis-Pseudoglioma Syndrome;OPPG)、結膜下出血、虹膜紅變、眼部新生血管性疾病、新生血管性青光眼、色素性視網膜炎(RP)、高血壓視網膜病變、視網膜血管瘤增生、黃斑部毛細管擴張、虹膜新生血管、眼內新生血管、視網膜變性、囊樣黃斑部水腫(CME)、脈管炎、視神經乳頭水腫、視網膜炎、結膜炎(包括感染性結膜炎及非感染性(例如過敏性)結膜炎)、雷伯氏先天性黑蒙(Leber congenital amaurosis)、葡萄膜炎(包括感染性及非感染性葡萄膜炎)、脈絡膜炎、眼部組織漿菌病、瞼炎、乾眼、創傷性眼損傷及薛格連氏病(Sjögren's disease)。
- 如請求項37之方法,其中該眼部疾病或病症為青光眼、AMD或DME。
- 如請求項31至39中任一項之方法,其中該多肽或該醫藥組合物係經玻璃體內、經眼、眼內、近鞏膜、球筋膜囊下、脈絡膜上、局部表面(topically)、靜脈內、肌肉內、皮內、經皮(percutaneously)、動脈內、腹膜內、病灶內、顱內、關節內、前列腺內、胸膜內、氣管內、鞘內、鼻內、陰道內、直腸內、瘤內、腹膜、腦室內、皮下、結膜下、囊泡內、經黏膜、心包內、臍內、眶內、經口、穿皮(transdermally)、藉由吸入、藉由注射、藉由滴眼劑、藉由植入、藉由輸注、藉由連續輸注、藉由直接局部化灌注浸泡目標細胞、藉由導管、藉由灌洗、以乳膏或以脂質組合物形式投與。
- 一種活化有需要之個體中之Tie2的方法,其包含向該個體投與有效量的如請求項1至22中任一項之多肽、如請求項29之細胞、如請求項23至25中任一項之核酸、如請求項26及27中任一項之載體及/或如請求項28之蛋白質複合物。
- 如請求項31至41中任一項之方法,其中該方法進一步包含投與第二藥劑。
- 如請求項42之方法,其中該第二藥劑係選自抗體、抗血管生成劑、細胞介素、細胞介素拮抗劑、皮質類固醇及鎮痛劑。
- 如請求項42之方法,其中該抗血管生成劑為VEGF拮抗劑或VE-PTP抑制劑。
- 如請求項42之方法,其中該VEGF拮抗劑為抗VEGF抗體、抗VEGF受體抗體、可溶性VEGF受體融合蛋白、適體、抗VEGF DARPin®或VEGFR酪胺酸激酶抑制劑。
- 如請求項42之方法,其中該抗VEGF抗體為雷珠單抗(ranibizumab) (LUCENTIS®)、RTH-258或雙特異性抗VEGF抗體。
- 如請求項42之方法,其中該雙特異性抗VEGF抗體為抗VEGF/抗Ang2抗體。
- 如請求項42之方法,其中該抗VEGF/抗Ang2抗體為RG-7716。
- 如請求項42之方法,其中該可溶性VEGF受體融合蛋白為阿柏西普(aflibercept) (EYLEA®)。
- 如請求項42之方法,其中該適體為哌加他尼(pegaptanib) (MACUGEN®)。
- 如請求項42之方法,其中該抗VEGF DARPin®為培戈阿比西帕(abicipar pegol)。
- 如請求項42之方法,其中該VEGFR酪胺酸激酶抑制劑係選自由以下組成之群:4-(4-溴-2-氟苯胺基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉(ZD6474)、4-(4-氟-2-甲基吲哚-5-基氧基)-6-甲氧基-7-(3-吡咯啶-1-基丙氧基)喹唑啉(AZD2171)、凡塔藍尼(vatalanib) (PTK787)、西瑪米尼(semaxaminib) (SU5416)及SUTENT® (舒尼替尼(sunitinib))。
- 一種增強經由有需要之個體的眼中之習知流出道之水狀液流出的方法,其包含向該個體投與有效量的如請求項1至22中任一項之多肽、如請求項29之細胞、如請求項23至25中任一項之核酸、如請求項26及27中任一項之載體、如請求項28之蛋白質複合物、及/或如請求項30之醫藥組合物,藉此增強經由該個體之該眼中的該習知流出道之水狀液流出。
- 一種降低有需要之個體之眼內壓的方法,其包含向該個體投與有效量的如請求項1至22中任一項之多肽、如請求項29之細胞、如請求項23至25中任一項之核酸、如請求項26及27中任一項之載體、如請求項28之蛋白質複合物、及/或如請求項30之醫藥組合物,藉此降低該個體之眼內壓。
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US7081443B2 (en) * | 2002-05-21 | 2006-07-25 | Korea Advanced Institutes Of Science And Technology (Kaist) | Chimeric comp-ang1 molecule |
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