TWI600432B - 利用胜肽來治療與血管新生相關之疾病 - Google Patents
利用胜肽來治療與血管新生相關之疾病 Download PDFInfo
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Description
本發明是關於一種治療方法。更具體來說，本發明是關於利用一種源自橋粒芯糖蛋白2(desmoglein 2,Dsg2)之胜肽來治療血管新生相關疾病的方法。
血管新生(angiogenesis)是指由既有血管長出新的微血管。血管新生過程相當複雜，一般係由內源性因子、促(或刺激)血管新生因子及抗(或抑制)血管新生因子共同調控。已知有多種促血管新生因子參與調控血管新生，包含鹼性纖維母細胞生長因子(basic fibroblast growth factor,bFGF)、介白素-1(interleukin 1,IL-1)、介白素-4(IL-4)、介白素-6(IL-6)、介白素-8(IL-8)、血管內皮生長因子(vascular endothelial growth factor,VEGF)、乙型轉形生長因子-1(transforming growth factor beta 1,TGFb1)、基質金屬蛋白酶-2(matrix metalloproteinase-2,MMP-2)、基質金屬蛋白酶-9(MMP-9)、上皮生長因子(epidermal growth factor,EGF)、腫瘤壞死因子(tumor necrosis factor,TNF)、骨髓生長因
子(myeloid growth factor,MGF)、血管生成素(angiogenin)、纖維蛋白溶酶原活化劑(plasminogen activator)、蛋白酶(proteases)、肝細胞生長因子(hepatocyte growth factor)、類胰島素生長因子(insulin-like growth factor)、前列腺素E(prostaglandin E)、低氧(hypoxia)及巨噬細胞衍生P因子(macrophages derived P factor)。例示性的抗血管新生因子則包含干擾素(interferon)、凝血栓蛋白(thrombospondin)、血管抑制素(angiostatin)、內皮抑制素(endostatin)、介白素-10(IL-10)、介白素-12(IL-12)、血小管衍生因子(platelet-derived factor)、血管內皮生長抑制劑(vascular endothelial growth inhibitor,VEGI)、組織基質金屬蛋白酶抑制劑(tissue matrix metalloproteinase inhibitor,MMPI)及纖維蛋白溶酶原活化抑制劑(plasminogen activator inhibitor)。
血管中的內皮細胞在未受刺激時，係處於靜止未活化狀態；當受到一或多種促血管新生因子刺激後，則會活化並啟動下游的促血管新生反應，導致該些內皮細胞合成及釋放降解酵素(degrading enzyme)，進而造成內皮細胞移動及生長，最終分化產生新生血管。在健康個體中，血管新生現象僅發生於胚胎及胎兒的器官發生時期、女性生理週期、體組織修復、傷口修復及組織再生。然而，愈來愈多報導指出，血管新生亦會導致各式疾病。
與血管新生相關的疾病包含：(1)眼部血管
新生疾病(例如血管新生性老化黃斑退化、糖尿病視網膜病變及早產兒視網膜病變)，當新生血管侵入視網膜或角膜後，會破壞或壓迫視覺神經，造成不可逆的視力受損；(2)導致風濕性關節炎及退化性關節炎，位於軟骨下空間及血管通道內的細胞及軟骨細胞會分泌各式生長因子引發血管新生，進而造成滑膜炎(synovitis)並加重關節軟骨的損傷程度；(3)發炎反應及發炎相關疾病，在發炎時，發炎細胞激素(例如環氧合酶2(cyclooxygenase 2)、前列腺素E2(prostaglandin E2)及凝血脂素(thromboxane A2))、發炎細胞(例如巨噬細胞、T細胞及肥胖細胞)及缺氧誘發因子(hypoxia-inducible factor,HIF)會促進促血管新生因子的表現，產生血管新生，而該些新生的血管會進一步促進發炎細胞侵入發炎部位，使發炎反應持續惡化；(4)倫-奧-韋三氏病(Osler-Weber-Rendu disease)或遺傳出血性血管擴張症(hereditary hemorrhagic telangiectasia)等遺傳性疾病，在該些疾病中，往往會因多系統血管發育不良而引發嚴重出血；以及(5)腫瘤的形成及轉移，腫瘤細胞會分泌各式促血管新生因子造成血管新生，該些新生血管不但可以提供腫瘤細胞充足的氧氣及養份，亦於腫瘤轉移過程中扮演著不可或缺的角色。
有鑑於此，相關領域亟需一種可用以有效抑制血管新生及/或治療血管新生相關疾病的藥物及治療方法。
發明內容旨在提供本揭示內容的簡化摘要，以使閱讀者對本揭示內容具備基本的理解。此發明內容並非本揭示內容的完整概述，且其用意並非在指出本發明實施例的重要/關鍵元件或界定本發明的範圍。
本揭示內容部份是基於發明人首次發現一段源自橋粒芯糖蛋白2(desmoglein 2,Dsg2)的胜肽可有效抑制血管新生。因此，本揭示內容的第一態樣是關於該段源自Dsg2之胜肽的用途，其適用於製備一種可治療血管新生相關病狀及/或疾病的藥物。
有鑑於血管新生與各式疾病的發生及進程(例如惡化程度)相關，且基於該段源自Dsg2之胜肽具有抑制血管新生的功效，因此本揭示內容的第二態樣是關於一種治療方法，其係於一亟需治療之個體體內治療與血管新生相關的病狀及/或疾病。該方法包含對該個體投予一治療有效量的胜肽，以改善或緩解與該病狀及/或疾病相關的病徵。
依據本揭示內容不同的實施方式，該段源自Dsg2之胜肽至少90%相同於序列編號：1或序列編號：3的胺基酸序列。在某些實施方式中，該序列相同度至少95%。在一特定實施方式中，該段源自Dsg2之胜肽的序列與序列編號：1的胺基酸序列完全相同。在另一特定實施方式中，該段源自Dsg2之胜肽的序列與序列編號：3的胺基酸序列完全相同。
依據本揭示內容某些實施方式，該個體係一哺乳類動物，例如人類。
在不同的實施方式中，該與血管新生相關之病狀及/或疾病可以是或可以由眼部血管新生疾病、發炎或發炎疾病、腫瘤、腫瘤轉移、感染、心血管疾病或受傷所導致。
例示性的眼部血管新生疾病包含，但不限於，視網膜血管新生疾病(retinal neovascular disease)、血管新生性老化黃斑退化(neovascular age-related macular degeneration)、少年黃斑退化(juvenile macular degeneration)、糖尿病視網膜病變(diabetic retinopathy)、早產兒視網膜病變(retinopathy of prematurity)、角膜移植排斥(corneal graft rejection)、角膜損傷(corneal diseases)、血管新生性青光眼(neovascular glaucoma)、晶狀體後纖維組織增生(retrolental fibroplasia)、結膜炎(conjunctivitis)、角膜炎(keratitis)、紅變症(rubeosis)、視網膜炎(retinitis)、脈絡膜炎(choroiditis)、維生素A缺乏(Vitamin A deficiency)、隱形眼鏡超戴(contact lens overwear)、翼狀胬肉(pterygium)、泡性角結膜炎(phylectenulosis)、化學灼傷(chemical burns)、鞏膜炎(scleritis)、特芮安氏角膜邊緣性退化(Terrien's marginal degeneration)、視網膜剝離(retinal detachment)、睫狀體扁平部炎(pars planitis)、伊爾斯氏病(Eales disease)及雷射後併發症。
發炎或發炎疾病包含，但不限於，風濕性關節炎(rheumatoid arthritis)、退化性關節炎
(osteoarthritis)、牛皮癬(psoriasis)、薛格連氏症候群(sjogren’s syndrom)、痤瘡(acne rosacea)、全身性紅斑狼瘡(systemic lupus erythematosus,SLE)、韋格納結節病(Wegener’s sarcoidosis)、多發性動脈炎(polyarteritis)、硬皮病(scleroderma)、克隆氏病(Crohn's disease)及巴東蟲症(bartonellosis)。
可利用本發明方式治療的腫瘤包含肺癌(lung carcinoma)、乳癌(breast carcinoma)、卵巢癌(ovarian carcinoma)、皮膚癌(skin carcinoma)、大腸直腸癌(colon carcinoma)、膀胱癌(urinary bladder carcinoma)、肝癌(liver carcinoma)、胃癌(gastric carcinoma)、腎癌(kidney carcinoma)、前列腺癌(prostate cancer)、胰臟癌(pancreatic cancer)、腎細胞癌(renal cell carcinoma)、鼻咽癌(nasopharyngeal carcinoma)、鱗狀細胞癌(squamous cell carcinoma)、甲狀腺乳突癌(thyroid papillary carcinoma)、子宮頸癌(cervical carcinoma)、小細胞肺癌(small cell lung carcinoma)、非小細胞肺癌(non-small cell lung carcinoma)、頭頸部鱗狀細胞癌(head and neck squamous cell cancer)、腦癌(brain tumor)、肉瘤(sarcomas)、黑色素瘤(melanoma)、血管瘤(hemangioma)及血癌(leukemia)。
本發明方法亦可用以治療細菌感染、病毒感染、真菌感染或原蟲感染。
心血管疾病則包含動脈硬化(atherosclerosis)、心肌血管新生(myocardial angiogenesis)、高度黏稠症候群(hyperviscosity
syndromes)、靜脈阻塞(vein occlusion)、動脈阻塞(artery occlusion)、頸動脈阻塞性疾病(carotid obstructive disease)及倫-奧-韋三氏病(Osler-Weber-Rendu disease)。
依據本揭示內容不同的實施方式，治療方法包含對一亟需治療之個體投予一有效量之源自Dsg2的胜肽，藉以產生抗血管新生功效及治療效果。
在參閱下文實施方式後，本發明所屬技術領域中具有通常知識者當可輕易瞭解本發明之基本精神及其他發明目的，以及本發明所採用之技術手段與實施態樣。
為讓本發明的上述與其他目的、特徵、優點與實施例能更明顯易懂，所附圖式之說明如下：第1圖的照片繪示出依據本揭示內容實施例1之Dsg2胜肽EC2區域的三維結構；第2圖的結果繪示出依據本揭示內容實施例1之人類內皮起源細胞(human endothelial progenitor cell,EPC)於基質膠(Matrigel)形成的血管管柱(左圖)，以及血管管柱的相對長度(右圖)；第3圖的照片繪示出依據本揭示內容實施例2之人類內皮起源細胞於基質膠中形成的血管管柱；第4圖的照片繪示出依據本揭示內容實施例3之人類臍靜脈內皮細胞(human umbilical vein
endothelial cell,HUVEC)於基質膠中形成的血管管柱；第5圖的照片繪示出依據本揭示內容實施例4之基質膠塞(Matrigel plug)上的新生血管；以及第6圖是依據本揭示內容實施例5所繪示之螢光照片，其中小鼠視網膜內皮細胞是先以與螢光素(fluorescein)接合之植物凝集素B4(isolectin B4)染色後，再利用螢光顯微鏡觀察染色結果。
為了使本揭示內容的敘述更加詳盡與完備，下文針對了本發明的實施態樣與具體實施例提出了說明性的描述；但這並非實施或運用本發明具體實施例的唯一形式。實施方式中涵蓋了多個具體實施例的特徵以及用以建構與操作這些具體實施例的方法步驟與其順序。然而，亦可利用其他具體實施例來達成相同或均等的功能與步驟順序。
雖然用以界定本發明較廣範圍的數值範圍與參數皆是約略的數值，此處已儘可能精確地呈現具體實施例中的相關數值。然而，任何數值本質上不可避免地含有因個別測試方法所致的標準偏差。在此處，「約」通常係指實際數值在一特定數值或範圍的正負10%、5%、1%或0.5%之內。或者是，「約」一詞代表實際數值落在平均值的可接受標準誤差之內，視本發明所屬技術領域中具有通常知識者的考量而定。除了實驗例之外，或除非另有明確的說明，當可理解此處所用的所有範圍、數
量、數值與百分比(例如用以描述材料用量、時間長短、溫度、操作條件、數量比例及其他相似者)均經過「約」的修飾。因此，除非另有相反的說明，本說明書與附隨申請專利範圍所揭示的數值參數皆為約略的數值，且可視需求而更動。至少應將這些數值參數理解為所指出的有效位數與套用一般進位法所得到的數值。
除非本說明書另有定義，此處所用的科學與技術詞彙之含義與本發明所屬技術領域中具有通常知識者所理解與慣用的意義相同。此外，在不和上下文衝突的情形下，本說明書所用的單數名詞涵蓋該名詞的複數型；而所用的複數名詞時亦涵蓋該名詞的單數型。
在本說明書中，「與血管新生相關的病狀及/或疾病」(angiogenesis-related condition and/or disease)一詞是指一種病理病狀及/或疾病，其中過量的血管新生會造成該病狀及/或疾病的進程或病徵的表現。
「胺基酸序列相同度百分比」(Percentage(%)amino acid sequence identity)一詞在本說明書是指在將一候選胜肽序列(candidate sequence)與一特定胜肽序列進行比對後，二序列間胺基酸殘基的相同百分比；在比對時，是將二序列排比，且若有必要，加入適當的間隙(gap)，藉以達到最大的相同度百分比，且不將保留性置換(conservative substitution)視為序列相同的一部份。可利用各式相關領域習知技藝人士所熟知的方法來進行比對，並決定二序列的相同百分比；舉例來說，可
以利用諸如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)等電腦軟體來進行比對分析。相關領域習知技藝人士可使用適當的參數(包含各式演算法)來測量比對，以於胺基酸全長序列中產生最大的比對序列。在本說明書中，二胺基酸序列間的序列比對是利用國家生物技術訊息中心(Nation Center for Biotechnology Information,NCBI)線上提供的Blastp(蛋白-蛋白BLAST)電腦軟體來進行分析。具體來說，一特定胺基酸序列A與一特定胺基酸序列B之間的胺基酸序列相同百分比(亦可表述為一特定胺基酸序列A與一特定胺基酸序列B具有某百分比的胺基酸序列相同度)是利用下列公式來計算：
其中X是經比對程式BLAST評比後，A與B序列間相互吻合的胺基酸殘基數量，Y則是A或B序列中(取較短者)胺基酸殘基的總數量。
本發明及本說明書亦包含蛋白/胜肽中胺基酸序列的微小變異，使胺基酸序列的變異維持至少90%，例如至少91%、92%、93%、94%、95%、96%、97%、98%及99%。特別是，保留性胺基酸取代亦包含於其中。保留性取代為具有相似/相關側鏈之胺基酸間的相互取代。一般來說，由基因編碼的胺基酸可分為四大類：(1)酸性胺基酸，即天門冬胺酸(aspartate)及麩胺酸(glutamate)；(2)鹼性胺基酸，即離胺酸(lysine)、精胺酸(arginine)
及組胺酸(histidine)；(3)非極性胺基酸，即丙胺酸(alanine)、纈胺酸(valine)、白胺酸(leucine)、異白胺酸(isoleucine)、脯胺酸(proline)、苯丙胺酸(phenylalanine)、甲硫胺酸(methionine)及色胺酸(tryptophan)；以及(4)非帶電極性胺基酸，即甘胺酸(glycine)、天冬醯胺酸(asparagine)、麩醯胺(glutamine)、色胺酸(cysteine)、絲胺酸(serine)、蘇胺酸(threonine)及酪胺酸(tyrosine)。較佳的分類是：絲胺酸及蘇胺酸係屬脂肪羥基(aliphatic-hydroxy)類；天冬醯胺酸及麩醯胺係屬含醯胺(amide-containing)類；丙胺酸、纈胺酸、白胺酸及異白胺酸係屬脂肪類；而苯丙胺酸、色胺酸及酪胺酸則屬芳香(aromatic)類。舉例來說，當可想見若以異白胺酸或纈胺酸取代白胺酸、以麩胺酸取代天門冬胺酸、以絲胺酸取代蘇胺酸，或是以一結構相似的胺基酸取代另一胺基酸時，並不會造成分子結合或蛋白特性的顯著改變，特別是當該取代位置不是位於骨架區域時，胺基酸之間的取代更不會影響上述特性。可藉由檢測胜肽衍生物之特定活性來了解一胺基酸的改變是否可形成一具功能性的胜肽。可利用相關領域習知技藝人士所熟知的方法來製備蛋白/胜肽的片段或其異構物。蛋白/胜肽的片段或其異構物之較佳的氨基末端及羧基末端是位於功能性區域附近。
除非本說明書另有定義，否則「治療」(treatment)一詞是指可產生一藥學上及/或生理上期望功效的治癒或緩解療法。較佳的情況是，該功效係可
部份或完全治癒血管新生相關之病狀及/或疾病。此外，「治療」(treatment)一詞於本說明書中亦指對一個體施用或投予本發明源自Dsg2之胜肽或包含該胜肽的藥物，其中該個體患有與血管新生相關之病狀及/或疾病、相關病徵、次要病徵或症狀，藉以達到部份或完全減輕、減緩、治癒疾病、延遲發病、抑制病程發展、降低疾病嚴重性，及/或降低一或多個血管新生相關病狀及/或疾病之相關病徵、症狀、或次要病徵的發生。
「有效量」(effective amount)在此處係指足以產生期望療效反應的藥物用量。具體的有效量取決於多種因素，如欲治療的特定狀況、患者的生理條件(如患者體重、年齡或性別)、接受治療的哺乳動物或動物的類型、治療持續時間、目前療法(如果有的話)的本質以及所用的具體配方和化合物或其衍生物的結構。有效量亦指一種化合物或組合物，其治療利益效果超越其毒性或有害影響。舉例來說，可將有效量表示成藥物的總重量(譬如以克、毫克或微克為單位)，或表示成藥物重量與體重之比例(其單位為毫克/公斤(mg/kg))。亦或是，有效量可以醫藥組合物中活性成份的濃度來表示，例如莫耳濃度(molar concentration)、重量濃度(mass concentration)、體積濃度(volume concentration)、重量莫耳濃度(molality)、莫耳分率(mole fraction)、重量分率(mass fraction)及混合比例(mixing ratio)。習知技藝者可依據動物模式的劑量來計算藥物(如本揭示內容之奈米粒子)的人體等效劑量(human equivalent dose,
HED)。舉例來說，習知技藝者可依據美國食品藥物管理局(US Food and Drug Administration,FDA)所公告之「估算成人健康志願者在初始臨床治療測式之最大安全起始劑量」(Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers)來估算人體使用之最高安全劑量。
「治療有效量」(therapeutically effective amount)一詞在本說明書是指一活性物質或包含該活性物質之藥物，在將其投予至需要治療之個體後，足以於該個體產生治療反應的劑量。一治療有效量亦指一活性物質或包含該活性物質之藥物，其治療利益效果超越其毒性或有害影響。
「個體」(subject)一詞是指包含人類的動物，其係依據本揭示內容之方法，能接受本揭示內容之源自Dsg2之胜肽的治療。除非特定指出，否則「個體」(subject)一詞同時意指男性及女性，且可以是任何年齡，例如兒童或成人。
本發明是基於發明人首次發現一源自人類橋粒芯糖蛋白2(desmoglein 2,Dsg2)的胜肽可有效減少血管新生。Dsg2屬於橋粒黏附蛋白(desmosomal cadherin)的一種，已知橋粒黏附蛋白會調控各式生物反應，例如細胞附著、形態發生、細胞骨架組織及細胞排列/移動；此外，橋粒黏附蛋白亦與癌症等各式疾病的生長及進程相關。在血管新生的訊息傳導路徑中，Dsg2扮演著重要的角色；多項研究已指出，利用Dsg2-小干擾核醣核酸
(Dsg2-siRNA)來抑制Dsg2的表現，可減少肌動蛋白應力纖維(actin stress fiber)形成、活體外血管管柱生成及活體內血管新生作用。
美國專利公開號2012/0276082(以下簡稱‘082公開案)揭示了某些源自Dsg2的小胜肽片段可減少細胞的上皮-間質轉型(epithelial-mesenchymal transition,EMT)。上皮-間質轉型是一種細胞轉型過程，其中細胞附著性的減少會導致細胞移動性的增加，進而造成細胞具有間葉細胞的特性。除了與中胚層及神經管的形成相關外，上皮-間質轉型亦於腫瘤的進程、侵犯及轉移過程中扮演著重要的角色。然而，‘082公開案並未提及任何關於源自Dsg2之小胜肽片段於抗血管新生方面的功效。此外，本申請案發明人意外發現本揭示內容之源自Dsg2的小胜肽片段(例如，序列編號：1或序列編號：3的胜肽)可有效抑制血管新生，且相較於一已知的血管新生抑制劑-貝伐單抗(Bevacizumab，商品名為癌思停，Avastin，購買自基因科技/羅氏)而言，序列編號：1的胜肽具有更為顯著的抗血管新生功效。
因此，本揭示內容的第一態樣是關於源自Dsg2之胜肽的用途，其係可用以製備一種治療血管新生相關病狀及/或疾病的藥物。該源自Dsg2之胜肽及/或包含該胜肽的藥物可進一步應用於相關治療方法，包含用以抑制一個體體內血管新生的治療方法，以及用以治療血管新生相關病狀及/或疾病的治療方法。
依據本揭示內容不同的實施方式，該用以治
療血管新生相關病狀及/或疾病的治療方法包含投予所需個體一治療有效量的胜肽，藉以抑制該個體標的位置的血管新生並產生治療功效，其中該肽胜至少90%相同於序列編號：1或序列編號：3的胺基酸序列。
在本揭示內容不同的實施方式中，該源自Dsg2之胜肽至少90%相同於序列編號：1或序列編號：3的胺基酸序列；舉例來說，二者的相同度可以是90%、91%、92%、93%、94%、95%、96%、97%、98%、99%或100%。較佳的情況是，相同度至少為95%。在一特定實施方式中，該段源自Dsg2之胜肽100%相同於序列編號：3的胺基酸序列。最佳的情況是，該段源自Dsg2之胜肽100%相同於序列編號：1的胺基酸序列。
本發明之源自Dsg2的胜肽可以任何習知技藝人士所熟知的方法來製備，例如加上α-氨基團之叔丁氧基羰基(tert-butyloxycarbonyl,t-BOC)或芴甲氧羰基(fluorenylmethyloxycarbonyl,FMOC)保護基之合成方法。二種合成方法皆是將單一胺基酸加至由胜肽C端起始的各步驟中。本發明胜肽亦可由習知技藝人士所熟知的固相胜肽合成法(solid phase peptide synthesis method)來製備。
本發明源自Dsg2的胜肽可於活體內(in vivo)、離體(ex vivo)或活體外(in vitro)抑制血管新生。血管新生是一種相當複雜的過程，包含了基底膜分解、內皮細胞及/或內皮起源細胞增生、內皮細胞及/或內皮起源細胞移動，以及血管管柱形成等步驟。內皮細胞是
構成血管內部的細胞；在血管新生過程中，胞外基質分解會將內皮細胞由基底膜釋放出來。內皮起源細胞是一群少量循環於血液中的細胞，可分化為內皮細胞。在血管新生過程中，內皮細胞及內皮起源細胞會朝向刺激源移動，進而排列及分支，最終形成血管的管狀多邊網形結構。各步驟皆可作為阻斷血管新生的標的，並利用不同的活體外試驗來分析測量。舉例來說，用以測量細胞增生的活體外試驗可以是胸腺核苷結合試驗(thymidine incorporation assay)、台酚藍染色(trypan blue staining)、MTT試驗或流式細胞儀分析。用以測定細胞移動的活體外試驗包含博登細胞爬行分析(Boyden chamber)；細胞移動試驗(cell movement assay)，其又稱吞噬動力軌跡試驗(phagokinetic track assay)；及孔隙閉合試驗(gap closure assay)，其又稱傷口癒合試驗(wound healing assay)。至於在測量內皮細胞形成三維結構(即血管管柱)的能力方面，通常係將細胞種植於與胞外基質相似的成份上(例如Engelbreth-Holm-Swarm,EHS基質)，再利用電子顯微鏡來檢測分析緊密連結(tight junction)的形成。除了活體外試驗外，亦可使用不同的離體及活體內試驗來檢測血管新生；相較於活體外試驗，該些離體及活體內試驗可提供與實際血管新生反應更為相似的測量方式。離體試驗包含主動脈環試驗(aortic ring assay)及雛雞主動脈弧試驗(chick aortic arch assay)；而活體內試驗則包含雛雞絨毛尿膜囊膜試驗(chick chorioallantoic membrane assay,CAM assay)、基質膠塞試驗(Matrigel plug assay)、海棉植入試驗(sponge
implantation assay)、角膜血管新生試驗(corneal angiogenesis assay)及視網膜血管新生試驗(retinal angiogenesis assay)。
在本揭示內容中，係利用不同的方法來檢測本發明源自Dsg2之胜肽的抗血管新生功效。依據一實施方式，係利用血管管柱形成試驗來進行檢測；其中本發明源自Dsg2之胜肽可減少內皮細胞或內皮起源細胞形成血管管柱的長度。
依據本揭示內容另一實施方式，係利用基質膠塞來進行檢測，其中該基質膠塞是一凝膠狀的EHS蛋白混合物，與生物組織中的胞外基質組成相似。在該實施方式中，本發明源自Dsg2之胜肽可抑制基質膠塞中血管的生成。
依據本揭示內容再另一實施方式，係利用視網膜血管新生試驗來進行檢測；其中本發明源自Dsg2之胜肽可有效地抑制視網膜血管新生。
依據上述任一實施方式，各種試驗皆係投予一有效量的本發明胜肽，其中該有效量足以產生抗血管新生之功效。
依據本揭示內容某些實施方式，本發明源自Dsg2之胜肽在抑制內皮細胞/內皮起源細胞增生、移動及形成血管管柱的適用劑量約為每毫升0.1-10毫克；亦即，該濃度可以是每毫升0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1.0、2.0、3.0、4.0、5.0、6.0、7.0、8.0、9.0或10毫克。較佳的情況是，濃度約為每毫升0.5-5毫
克。在本揭示內容一特定實施方式中，是利用每毫升0.5-1毫克之源自Dsg2的胜肽來進行抑制實驗。
至於在抑制活體內血管新生的部份，本發明源自Dsg2之胜肽的治療有效量約為每公斤個體體重0.1-100毫克；舉例來說，依照不同的治療狀況及個體的身理狀況，治療有效量可以是每公斤體重0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1.0、2.0、3.0、4.0、5.0、6.0、7.0、8.0、9.0、10.0、20.0、30.0、40.0、50.0、60.0、70.0、80.0、90.0或100.0毫克。依據一實施方式，是投予個體每公斤體重0.5-50毫克之本發明胜肽。在一特定實施方式中，投予個體每公斤體重0.5-10毫克之本發明胜肽即足以產生抑制血管新生的功效。
依據本揭示內容一實施方式，是將本發明胜肽投予至一患有血管新生相關病狀及/或疾病的個體；其中，本發明胜肽可有效抑制該個體之病理性血管新生，進而治療血管新生相關病狀及/或疾病，而不會影響該個體正常的生理性血管新生(即體組織修復、傷口修復及組織再生)。
癌思停是一種已廣泛使用的血管新生抑制劑，可阻斷由血管內皮生長因子所引發的訊息傳遞路徑，據以抑制新生血管的生長。癌思停已被美國食品藥物管理局認證，可用以治療不同的癌症，包含大腸直腸癌、肺癌、腎臟癌、卵巢癌及腦部膠質母細胞瘤。依據本揭示內容一特定實施方式，相較於癌思停，本發明胜肽具有更加顯著的抗血管新生功效。
除了本發明胜肽，利用該胜肽所製備的藥物更可包含一藥學上可接受的載體，藉以提供一種適用於活體動物(包含人類)的藥劑形式。舉例來說，該藥學上可接受的載體可以是液態、凝膠、乳膏、軟膏、黏合劑、羊膜、皮膚替代品、人工皮膚或皮膚相似物。例示性之替代品包含明膠、賦形劑、無熱原水、等張生理食鹽水及磷酸根緩衝溶液。
選擇與本發明胜肽併用之藥學上可接受的載體基本上是取決於藥物所期望的產品形式。本發明藥物可以經由特定部位(例如局部塗抹、結膜下注射、關節內注射及皮內注射)或全身性(例如血液注射及表皮下注射)的方式投予至個體體內。
適用於局部塗抹之藥學上可接受的載體包含該些適用於液態(包含液體及乳液)、乳膏及凝膠之藥學上可接受的載體。進一步來說，該藥物係為無菌且可以是劑量單位形式(例如，適用於眼部使用)。該藥物可以包裝成一適用於計量應用的形式，例如一配有滴管的容器。在一實施方式中，該藥學上可接受的載體包含一眼部可接受之藥用賦形劑。在一實施方式中，該藥物是以生理食鹽水作為載體配製而成的溶液。在另一實施方式中，該藥物是一包含適當濃度之本發明胜肽的軟膏。較佳的情況是，利用適當的緩衝系統使該溶液及軟膏的酸鹼值維持在pH 4.5到8.0之間；其中又以中性pH為最優。或者是，本發明胜肽可以製備成可用以傷口處的羊膜、皮膚替代品、人工皮膚或皮膚相似物。
若是採注射途徑(包含局部、腸內及腸外注射)，可利用一藥學上可接受的載體來配製本發明胜肽，其中該藥學上可接受的載體可以是與血液等張的無菌水溶液。在配製上，是將固體活性成份溶解或懸浮於包含生理相容性物質(例如氯化鈉及甘氨酸)且具有與生理狀態相容的緩衝酸鹼值之水中，再將製備出的水溶液進行無菌處理。
其餘適用於製備無菌注射液或懸浮液的稀釋液或溶劑包含，但不限於，1,3-丁二醇(1,3-butanediol)、甘露醇(mannitol)、水及林格氏液(Ringer’s solution)。肪脂酸，例如油酸(oleic acid)及其甘油酯衍生物(glyceride derivatives)，或是自然中藥學上可接受的油，例如橄欖油(olive oil)或蓖麻油(castor oil)，亦可用以製備注射液。該些油溶液或懸浮液也可以包含乙醇稀釋劑或羧甲纖維素(carboxymethyl cellulose)或相似的分散劑(dispersing agents)。為配製目的，亦可使用常用的表面活化劑(surfactants)，例如聚山梨醇酯(Tweens)、聚山梨糖醇單油酸酯(Spans)、其他相似的乳化劑或常用於施予藥學上可接受劑型之生物可利用增強劑(bioavailability enhancers)。
本發明藥物亦可包含習知技藝人士所熟知的各式添加劑。舉例來說，可利用包含少量乙醇的溶劑來穩定某些藥物成份。其他適用之藥學上可接受的添加劑包含乳白劑(opacifiers)、抗氧化劑(antioxidants)、香料(fragrance)、著色劑(colorant)、膠凝劑(gelling agents)、
增稠劑(thickening agents)、穩定劑(stabilizers)及表面活性劑(surfactants)等。此外，亦可添加其餘試劑，例如抗菌劑來防止儲存物變質(即抑制酵母菌及黴菌等微生物的生長)。本發明藥物更可包含滲透增強劑(permeation enhancers)及/或減緩刺激添加劑(irritation-mitigating additives)。
依據本揭示內容某些實施方式，該個體是一哺乳類動物，例如人類。
可以本發明方法治療的血管新生相關疾病包含眼部血管新生疾病、發炎或發炎疾病、腫瘤、腫瘤轉移、感染、心血管疾病及受傷。本所屬領域具有通常知識者當可想見，上述疾病的分類僅為說明闡述之用，而非用以提供疾病的臨床分類。具體來說，在一特定疾病分類中描述的病症/疾病亦有可能符合另一種疾病分類的一般定義。舉例來說，本揭示內容是將角膜炎列舉為眼部血管新生疾病，然該疾病往往是由細菌、真菌或病毒感染，且與發炎反應相關。
目前已知有多種眼部病狀及/或疾病係與血管的過度生長相關；該些病狀及/或疾病包含，但不限於，視網膜血管新生疾病(retinal neovascular disease)、血管新生性老化黃斑退化(neovascular age-related macular degeneration)、少年黃斑退化(juvenile macular degeneration)、糖尿病視網膜病變(diabetic retinopathy)、早產兒視網膜病變(retinopathy of prematurity)、角膜移植排斥(corneal graft rejection)、角膜損傷(corneal
diseases)、血管新生性青光眼(neovascular glaucoma)、晶狀體後纖維組織增生(retrolental fibroplasia)、結膜炎(conjunctivitis)、角膜炎(keratitis)、紅變症(rubeosis)、視網膜炎(retinitis)、脈絡膜炎(choroiditis)、維生素A缺乏(Vitamin A deficiency)、隱形眼鏡超戴(contact lens overwear)、翼狀胬肉(pterygium)、泡性角結膜炎(phylectenulosis)、化學灼傷(chemical burns)、鞏膜炎(scleritis)、特芮安氏角膜邊緣性退化(Terrien's marginal degeneration)、視網膜剝離(retinal detachment)、睫狀體扁平部炎(pars planitis)、伊爾斯氏病(Eales disease)及雷射後併發症。
某些發炎病徵有可能會導致發炎部位的血管新生；因此，與血管新生相關的疾病亦包含某些發炎徵狀，例如風濕性關節炎(rheumatoid arthritis)、退化性關節炎(osteoarthritis)、牛皮癬(psoriasis)、薛格連氏症候群(sjogren’s syndrom)、痤瘡(acne rosacea)、全身性紅斑狼瘡(systemic lupus erythematosus,SLE)、韋格納結節病(Wegener’s sarcoidosis)、多發性動脈炎(polyarteritis)、硬皮病(scleroderma)、克隆氏病(Crohn's disease)及巴東蟲症(bartonellosis)。
血管新生往往在腫瘤的進程及轉移過程中扮演著重要的角色。例示性的腫瘤包含，但不限於，肺癌(lung carcinoma)、乳癌(breast carcinoma)、卵巢癌(ovarian carcinoma)、皮膚癌(skin carcinoma)、大腸直腸癌(colon carcinoma)、膀胱癌(urinary bladder
carcinoma)、肝癌(liver carcinoma)、胃癌(gastric carcinoma)、腎癌(kidney carcinoma)、前列腺癌(prostate cancer)、胰臟癌(pancreatic cancer)、腎細胞癌(renal cell carcinoma)、鼻咽癌(nasopharyngeal carcinoma)、鱗狀細胞癌(squamous cell carcinoma)、甲狀腺乳突癌(thyroid papillary carcinoma)、子宮頸癌(cervical carcinoma)、小細胞肺癌(small cell lung carcinoma)、非小細胞肺癌(non-small cell lung carcinoma)、頭頸部鱗狀細胞癌(head and neck squamous cell cancer)、腦癌(brain tumor)、肉瘤(sarcomas)、黑色素瘤(melanoma)、血管瘤(hemangioma)或血癌(leukemia)。
本發明發法的範疇亦包含由細菌、病毒、真菌或原蟲感染所造成的血管新生。
與血管新生相關的因子通常也有可能導致心血管疾病，例如動脈硬化(atherosclerosis)、心肌血管新生(myocardial angiogenesis)、高度黏稠症候群(hyperviscosity syndromes)、靜脈阻塞(vein occlusion)、動脈阻塞(artery occlusion)、頸動脈阻塞性疾病(carotid obstructive disease)或倫-奧-韋三氏病(Osler-Weber-Rendu disease)。
下文提出多個實驗例來說明本發明的某些態樣，以利本發明所屬技術領域中具有通常知識者實作本發明，且不應將這些實驗例視為對本發明範圍的限制。據信習知技藝者在閱讀了此處提出的說明後，可在不需過度解讀的情形下，完整利用並實踐本發明。此處所引
用的所有公開文獻，其全文皆視為本說明書的一部分。
材料及方法
源自Dsg2之胜肽
本發明源自Dsg2之胜肽具有序列編號：1的胺基酸序列(即KINATDADEPNTLNSKISYRC)，源自人類基因之控制組胜肽具有序列編號：2的胺基酸序列(即KNITAADEDNPLTSNKIYSR)，而另一源自Dsg2之IP10胜肽則具有序列編號：3的胺基酸序列(即IVSLEPAYPP)；二者皆是由台北基龍米克斯公司(Genimics BioSci &Tech,Taipei)合成。
細胞
人類臍靜脈內皮細胞(human umbilical vein endothelial cell,HUVEC)係購買自PromoCell(海德堡)。人類內皮起源細胞(human endothelial progenitor cell,EPC)係依據赫爾辛基宣言之原則，由健康捐贈者取出製備。本研究所有試驗皆是在台灣新北市馬偕紀念醫院的機構審查委員會認證許可下進行。
其他材料
基質膠是購買自富蘭克林湖的BD Bioscieces；癌思停則是購自南舊金山的基因科技/羅氏(Genetech/Roche)。
基質膠血管新生試驗
將總體積為200微升之基質膠加入24-孔盤，於37℃放置30分鐘使其聚合。將5×104細胞(人類內皮起源細胞或人類臍靜脈內皮細胞)種入置有基質膠的
24-孔盤後，分別加入Dsg2胜肽(每毫升0.25毫克、每毫升0.5毫克或每毫升1毫克)、控制組胜肽(每毫升1毫克)及癌思停(每毫升10微克)，並補入包含2%胎牛血清(fetal bovine serum,FBS)的MV2細胞培養液；將細胞培養於37℃、5%CO2的潮溼環境下24小時。各檢體皆是在同一24-孔盤中，以三重複的方式進行試驗，之後以徠卡相機(×40放大倍率)來偵測各檢體。
血管管柱的相對長度
相對於對照組的血管管柱長度是利用QWIN軟體，由5個隨機視野測檢管柱長度後，分析定量所得。各實驗皆重複超過三次。最後以平均值±標準差來表示三次實驗數據。
基質膠塞試驗
將0.5毫升、分別包含(1)每毫升60單位肝素(heparin)，(2)每毫升60單位肝素、每毫升10奈克血管內皮生長因子及生理食鹽水，(3)每毫升60單位肝素、每毫升10奈克血管內皮生長因子及每毫升1毫克之控制組胜肽，以及(4)每毫升60單位肝素、每毫升10奈克血管內皮生長因子及每毫升1毫克之Dsg2胜肽的生長因子減少液基質膠(growth factor-reduced liquid Matrigel)，以皮下注射的方式注入C57BL/6小鼠腹部中線周圍的皮下位置。注射7天後，犠牲小鼠，並取出基質膠塞進行後續分析。
血紅素含量
為分析血管新生，利用Drabkin試劑525
(Sigma-Aldrich)來測量基質膠塞中血紅素的含量。簡單來說，將基質膠塞加入包含紅血球溶解試劑的溶液後，於冰上放置24小時，使其再次液化。簡單離心後，取20微升的上清液加入100微升的Drabkin溶液。將混合液置於室溫30鐘，再測量混合液於540奈米的吸光值。利用基質膠塞的重量來基準化血紅素含量，最後以血紅素(微克)/基質膠塞(毫克)來表示。
動物實驗
將新生的C57BL/6小鼠飼養於一般常氧(normoxia)環境中，直到出生後第12天；該群小鼠為常氧組小鼠。氧氣引發視網膜病變組(oxygen-induced retinopathy,OIR)小鼠則是在出生後7天，與乳鼠(nursing mother)一起移至75%氧氣(相對於20.9%氧氣之常氧，75%氧氣為高氧環境)的環境中飼養5天，之後於出生後第12天移回常氧環境(相對高氧環境為一低氧環境)來模擬缺氧狀態，藉以促使視網膜血管新生。之後，將1微升之Dsg2胜肽(25微克)、控制組胜肽(25微克)及癌思停(10微克)分別以玻璃體內注射方式投予至出生後第12天的小鼠眼中。於出生後第17天犠牲小鼠，取出其眼球進行後續分析。
全覆式免疫螢光染色(Whole mount immunofluorescent staining)
將小鼠眼杯固定於4%三聚甲醛(paraformaldehyde)中2小時。由眼杯小心取出視網膜，再將視網膜置於與螢光素(fluorescein)接合之植物凝集
素B4(isolectin B4,Life technologies)中，於4℃作用至隔日。以Vectashield培養液(Vector Laboratories)覆蓋檢體後，利用蔡司LSM-510共軛焦顯微鏡以20×物鏡觀察檢體。藉由QWIN軟體分析記錄檢體之螢光量。
實施例1 確認Dsg2胜肽片段
利用SWISS-MODEL來預測Dsg2胜肽之EC2區域的三維結構。預測結果顯示，非-CAR區域包含三個具有固定殘基的環狀結構；其中，該固定殘基可能參與生物功能的調控。進一步利用Rasmol軟體來呈現Dsg2胜肽的EC2區域(如第1圖所示)；結果指出，基於EC2區域的三維結構，可將EC2區域分為包含EV10、KR20、IP10、VE10、YY15及AQ15等六個片段。
如第2圖所示，六個片段中的KR20及IP10片段在每毫升1.0毫克的濃度下，皆可有效抑制內皮起源細胞於基質膠中的血管新生(p<0.05)；其中，KR20片段具有更為顯著的抑制功效。因此，本發明源自Dsg2的胜肽主要是基於KR20的胺基酸序列，並與一半胱胺酸殘基接合所組成，組成的胜肽具有序列編號：1的胺基酸序列。
實施例2 源自Dsg2的胜肽可抑制內皮起源細胞的血管新生
首先利用基質膠血管新生試驗來檢測本發明源自Dsg2之胜肽對內皮起源細胞的抗血管新生功效。
如第3圖所示，本發明源自Dsg2之胜肽可顯著地抑制內皮起源細胞的血管新生，其中胜肽的濃度為
每毫升0.5毫克(即200μM)或每毫升1毫克(即400μM)。特別的是，相較於對照組，每毫升1毫克(400μM)之源自Dsg2的胜肽可減少50%以上的血管管柱形成，造成其血管管柱長度低於對照組血管管柱長度的50%(p<0.05)。
實施例3 源自Dsg2的胜肽可抑制人類臍靜脈內皮細胞的血管新生
進一步利用基質膠血管新生試驗來檢測本發明源自Dsg-2之胜肽對人類臍靜脈內皮細胞的抗血管新生功效。在本實施例中，亦包含一種在臨床上廣為使用的抗血管新生藥劑一癌思停，用以比對本發明源自Dsg-2之胜肽的抑制功效。
第4圖的結果指出，不論是本發明源自Dsg2的胜肽或是癌思停，二者皆可有效抑制人類臍靜脈內皮細胞於基質膠中的血管新生；相較之下，控制組胜肽則無任何的抑制效果。值得注意的是，相較於癌思停，本發明源自Dsg2之胜肽可更為有效地抑制血管管柱形成；該結果顯示，本發明源自Dsg2之胜肽可藉由抑制血管新生來達到治療視網膜血管新生的目的，係為一具有應用潛力的治療藥物。
實施例4 源自Dsg2的胜肽可抑制基質膠塞中的血管新生
在本實施例中，是利用基質膠塞試驗來檢測本發明源自Dsg2之胜肽的抗血管新生功效。一般來說，基質膠塞試驗是一種簡單的活體內技術，可用以偵測小
鼠體內移植膠塞中的新生血管，藉此評估促血管新生化合物及抗血管新生化合物的活體內抑制功效。
如第5圖所示，相較於生理食鹽水或控制組胜肽，本發明源自Dsg2之胜肽可抑制基質膠塞中新生血管的形成。分析結果進一步證明，相較於以生理食鹽水或控制組胜肽處理的基質膠塞，經本發明源自Dsg2之胜肽處理後的基質膠塞，其內血紅素含量將會顯著地下降(p<0.05)。
實施例5 源自Dsg2的胜肽可抑制OIR動物模式之視網膜血管新生
視網膜低/缺氧被視為是導致視網膜血管新生的主因之一，進而產生視網膜病變，造成失明及視力減退。在本實施例中，係利用動物模式(OIR，用以模擬缺氧模式)來檢測本發明源自Dsg2之胜肽的抗血管新生功效，其中該動物模式是將小鼠飼食於高氧環境再轉為常氧環境，使其產生視網膜血管新生，再投予特定的治療。利用與螢光素接合之植物凝集素B4偵測分析，其中植物凝集素B4可辨識並專一結合至內皮細胞上。
如第6圖所示，OIR組小鼠會產生視網膜的血管新生，而飼養於常氧環境下的小鼠(對照組)則不會。此外，相較於生理食鹽水或控制組胜肽，本發明源自Dsg2之胜肽及癌思停皆可顯著地抑制缺氧模式所引發的血管新生(p<0.01)。值得注意的是，本發明源自Dsg2之胜肽的抗血管新生功效更優於癌思停的抗血管新生功效。
總結上述，該些結果指出，本發明源自Dsg2之胜肽可有效抑制活體外及活體內的血管新生。此外，結果亦顯示，本發明源自Dsg2之胜肽的抗血管新生功效與已知的抗血管新生藥劑相當。有鑑於血管新生與多種病症及/或疾病相關，本發明藥物及/或方法將可藉由抑制血管新生來治療不同類型的病症及/或疾病。
雖然上文實施方式中揭露了本發明的具體實施例，然其並非用以限定本發明，本發明所屬技術領域中具有通常知識者，在不悖離本發明之原理與精神的情形下，當可對其進行各種更動與修飾，因此本發明之保護範圍當以附隨申請專利範圍所界定者為準。
Claims (2)
- 一種源自橋粒芯糖蛋白2之胜肽的用途，其係用以製備一種可治療眼部血管新生疾病的藥物，其中該源自橋粒芯糖蛋白2之胜肽具有序列編號：1的胺基酸序列，且該眼部血管新生疾病是視網膜血管新生疾病(retinal neovascular disease)、血管新生性老化黃斑退化(neovascular age-related macular degeneration)、少年黃斑退化(juvenile macular degeneration)、糖尿病視網膜病變(diabetic retinopathy)、早產兒視網膜病變(retinopathy of prematurity)、角膜移植排斥(corneal graft rejection)、角膜損傷(corneal diseases)、血管新生性青光眼(neovascular glaucoma)、晶狀體後纖維組織增生(retrolental fibroplasia)、結膜炎(conjunctivitis)、角膜炎(keratitis)、紅變症(rubeosis)、視網膜炎(retinitis)、脈絡膜炎(choroiditis)、維生素A缺乏(Vitamin A deficiency)、隱形眼鏡超戴(contact lens overwear)、翼狀胬肉(pterygium)、泡性角結膜炎(phylectenulosis)、化學灼傷(chemical burns)、鞏膜炎(scleritis)、特芮安氏角膜邊緣性退化(Terrien's marginal degeneration)、視網膜剝離(retinal detachment)、睫狀體扁平部炎(pars planitis)、伊爾斯氏病(Eales disease)或雷射後併發症。
- 如請求項1所述之用途，其中該眼部血管新生疾病是視網膜血管新生疾病。
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