TWI569804B - 一種用以治療a型流感病毒感染的方法 - Google Patents
一種用以治療a型流感病毒感染的方法 Download PDFInfo
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- TWI569804B TWI569804B TW104144260A TW104144260A TWI569804B TW I569804 B TWI569804 B TW I569804B TW 104144260 A TW104144260 A TW 104144260A TW 104144260 A TW104144260 A TW 104144260A TW I569804 B TWI569804 B TW I569804B
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Description
本揭示內容大致上是關於治療感染的領域。更具體來說,本揭示內容是關於一種用以治療或預防A型流感病毒感染的方法。
A型流感病毒 (influenza A virus, IAV)是一種負向(negative-sense)、單股(single-stranded)且分段(segmented)的RNA病毒。季節性的IAV感染具有高發病率及高死亡率,每年導致全球約250,000–500,000個體死亡,並造成全美超過35,000個體死亡。對健康的孩童及成人而言,IAV感染通常僅會造成中等嚴重程度的病狀。然而,對免疫功能不足或缺損(immunocompromised)的個體(例如不健康之個體或老年人)來說,IAV感染可能會造成非常嚴重的病狀。其中一種與IAV相關且會導致個體高死亡風險的病徵為慢性肺部疾病(例如氣喘(asthma)、肺氣腫(emphysema)、慢性支氣管炎(chronic bronchitis)、支氣管擴張症(bronchiectasis)或囊腫纖維化(cystic fibrosis)),其多數是由過量發炎反應所造成。已知除了可作為IAV感染及複製之主要標的細胞的支氣管及肺泡上皮細胞外,巨噬細胞(macrophage)亦在由IAV所引發之肺部發炎反應中扮演著重要的角色。一旦遭受IAV感染,巨噬細胞會快速地產生第I型干擾素(type I interferon,例如干擾素-α及干擾素-β)、促發炎細胞激素(pro-inflammatory cytokine,例如TNF-α、IL-6及IL-1β)及趨化激素(chemokine,例如MCP-1、MIP-1α、RANTES及IP-10),進而吸引白血球浸潤至肺部組織,造成組織損傷、水腫(edema)及肺功能障礙。因此,巨噬細胞常被認為對由IAV所引發的肺部損傷及個體死亡具有關鍵性的影響。
誘餌受體3 (Decoy receptor 3, DcR3)亦稱為腫瘤壞死因子受體超家族成員6B (tumor necrosis factor receptor superfamily member 6B, TNFRSF6B)、TR6或M68,是TNF受體超家族的一員。由於缺少跨膜域(transmembrane domain),DcR3會表現為可溶性蛋白的形式。目前已知該蛋白在不同的訊號傳遞路徑中扮演著調控者的角色,且參與不同的細胞作用:(1)抑制由Fas所引發之細胞死亡;(2)抑制由LIGHT所傳遞的T細胞活化;(3)引發血管新生;以及(4)調控單核球(monocyte)活化及分化為樹突細胞(dendritic cell)、巨噬細胞及蝕骨細胞(osteoclast)。此外,亦發現DcR3會過量表現在不同的腫瘤及發炎組織。
由於IAV感染持續對人類造成重大的威脅,且目前尚不清楚該如何預防或調控因感染所造成的組織損傷,相關領域因此亟需一種經改良的方法,以治療或預防IAV感染,並據以使被感染之個體免於產生後續的組織損傷。
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。
本揭示內容的第一態樣是關於一種於一個體體內治療或預防IAV感染的方法。該方法包含對該個體投予一治療有效量之融合蛋白,其係包含一由序列編號:4所組成的第一胜肽及一與該第一胜肽連結之人類IgG1 Fc區域。
本揭示內容的另一態樣是關於一種用以減緩一有需要個體之肺部損傷的方法;具體來說,該個體係遭受IAV感染,且產生由IAV所引發之過量發炎反應。該方法包含對該個體投予一治療有效量之融合蛋白,其係包含一由序列編號:4所組成的第一胜肽及一與該第一胜肽連結之人類IgG1 Fc區域。
依據本揭示內容某些實施方式,該融合蛋白更包含一由序列編號:5所組成的第二胜肽,及一由序列編號:6所組成的第三胜肽,其中該第二及第三胜肽分別分別位於及連接於該由序列編號:4所組成之第一胜肽的上游及下游。
依據本揭示內容某些實施方式,該融合蛋白每劑投予劑量約為每公斤體重0.5到5毫克。在一較佳實施例中,該融合蛋白每劑投予劑量約為每公斤體重0.8到1毫克。依據本揭示內容其他實施方式,在一完整的療程中,該融合蛋白的總投予劑量約為每公斤體重1到10毫克;較佳的情況是,該融合蛋白的總投予劑量約為每公斤體重1.6到2毫克。
依據本揭示內容一實施方式,該融合蛋白可由口服(oral)、腸內(enteral)、鼻腔(nasal)、局部(topical)、穿透黏膜(transmucosal)或非口服(parenteral)方式投予至該個體。一般來說,非口服方式可以是肌肉注射(intramuscular injection)、靜脈注射(intravenous injection)或腹腔注射(intraperitoneal injection)。
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,此處已盡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。在此處,將數值範圍表示成由一端點至另一段點或介於二端點之間;除非另有說明,此處所述的數值範圍皆包含端點。
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,「胜肽」(peptide)一詞是指一至少具有二個胺基酸殘基的直鏈,其中該至少二個胺基酸殘基是以肽鍵(peptide bond)相互連接。組成胜肽的胺基酸可以是20種標準基因編碼胺基酸、其他自然產生的胺基酸、非自然產生的胺基酸或化學衍生的胺基酸,且可以以L形式之異構物(isomer)或D形式之異構物存在。在本揭示內容中,胜肽可以包含2到300個胺基酸殘基;較佳是包含2到260個胺基酸殘基。可由本所屬領域習知技藝人士熟知之慣用技術來製得胜肽。舉例來說,可以合成方式或經酵素切割自然或重組蛋白來製得胜肽。
「蛋白」(protein)及「多肽」(polypeptide)在本說明書為可互換的詞彙,係指一由一或多胜肽所組成的生物分子,而不論其轉譯後的修飾。蛋白中的各胜肽可以是一個次單元(subunit)。所述蛋白或多肽可以是自然或經修飾的形式,且可以具有生物活性或特性。
「融合蛋白」(fusion protein)一詞在本說明書是指二蛋白或肽胜的組合,其係可以共價交互作用、靜電交互作用、疏水性交互作用、親和鍵結等任一方式或形式連結,藉以維持蛋白/胜肽間之鍵結關係、防止在後續操作步驟中鍵結的斷裂,且大致上不會改變蛋白的結合特性。本發明較佳的融合蛋白是由重組基因編碼而成的胜肽,其中該重組基因包含二或多個不同基因的部分序列;相互連接之基因的編碼序列是位於同一閱讀框架中,即基因表現裝置(genetic apparatus)會將基因融合視為單一個基因。此類型的融合蛋白亦稱為雜合蛋白(hybrid protein)或嵌合蛋白(chimeric protein)。
「Fc區域」(Fc region)及「可結晶區域片段」(fragment crystallizable region) 在本說明書為可互換的詞彙,係指一免疫球蛋白 (immunoglobulin,例如IgG1、IgG2、IgG3或IgG4) 重鏈的C端區域,包含自然序列Fc區域及變異Fc區域。即使一免疫球蛋白重鏈之Fc區域的邊界可能不盡相同,人類IgG重鏈Fc區域常是指由Cys226位置或Pro230位置之胺基酸殘基延伸至其C端的片段。Fc區域可以包含絞鏈區域(hinge region,例如自然或經修飾之絞鏈區域)之任何部分。Fc可以源自任一種包含人類之哺乳動物,且可經轉譯後修飾(例如醣化)。在一非限定之實施例中,Fc區域是人類IgG1的區域,且具有序列編號:7的胺基酸序列。
本所屬領域習知技藝人士當可了解「發炎」(inflammation)一詞包含任何由感染引發之局部保護反應所造成的症狀,通常具有明顯的熱、腫、痛、紅、血管擴張、血流增加、白血球浸潤感染部位、功能受損及/或任何已知與發炎症狀相關的病徵。在本說明書及申請專利範圍中,「發炎」(inflammation)一詞是指促發炎介質(例如細胞、細胞激素及趨化激素)於個體組織及/或器官(例如肺臟)中的累積、增加及/或誘發。
「有效量」(effective amount)一詞於此是指一種足以產生一期望治療反應的成份的使用量。一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。具體的有效量取決於多種因素,如所欲治療的特定狀況、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種類、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。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)。具體來說,「治療有效量」(therapeutically effective amount)一詞在本說明書是指足以減緩個體體內與IAV感染相關之症狀的融合蛋白劑量。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。
「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融合蛋白的治療。除非特定指出,否則「個體」(subject)一詞同時意指男性及女性。
有鑑於IAV感染會造成嚴重的組織損傷,進而威脅人類健康,本揭示內容之主旨為提供一種可保護人類免於罹患與IAV感染相關之病狀的方法。
據此,本揭示內容的第一態樣是關於一種可於一個體體內治療或預防A型流感病毒感染的方法。該方法包含對該個體投予一治療有效量之融合蛋白,其係包含一功能性胜肽及一人類IgG1 Fc區域。依據本揭示內容某些實施方式,該功能性胜肽是人類DcR3蛋白的硫酸肝素蛋白多醣結合域(heparin sulfate proteoglycan binding domain, HBD)胜肽。為製備該種包含HBD胜肽及人類IgG1 Fc區域的融合蛋白(以下標記為HBD.Fc),將用以編碼HBD胜肽之序列編號:1的多核苷酸以同閱讀框架方式(in frame)建構於表現載體中用以編碼人類IgG1 Fc區域之序列編號:3之多核苷酸的5’端。當可想見,該表現載體可以是任何適用於表現外源性基因的表現載體;舉例來說,該載體可以是pcDNA3或pBacPAK9。在本揭示內容一實施方式中,用以表現融合蛋白HBD.Fc的表現載體是pcDNA3,可將其轉染至哺乳動物細胞以表現融合蛋白。依據實驗室常用的表現系統,該哺乳動物細胞可以是FreeStyle 293-F細胞。製得的融合蛋白HBD.Fc因此包含一HBD胜肽及一人類IgG1 Fc區域,其係分別具有序列編號:4及7的胺基酸序列。
依據本揭示內容其他實施方式,該融合蛋白包含一人類DcR3蛋白及一人類IgG1 Fc區域(以下標記為DcR3.Fc)。與上述建構步驟相似,將用以編碼DcR3蛋白之序列編號:2的多核苷酸以同閱讀框架方式(in frame)建構於表現載體中用以編號人類IgG1 Fc區域之序列編號:3之多核苷酸的5’端。如同上述,表現載體可以是任何適用於表現外源性基因的表現載體。在本揭示內容一實施例中,用以表現融合蛋白DcR3.Fc的表現載體是pBacPAK9,可將其轉染至昆蟲細胞以表現融合蛋白。例示性之適合表現外源性基因的昆蟲細胞包含,但不限於,Sf9、Sf21及High-Five細胞。依據一特定實施例,該昆蟲細胞是Sf21細胞。製得的融合蛋白DcR3.Fc因此包含彼此相互連結之DcR3蛋白及人類IgG1 Fc區域;更具體來說,該人類IgG1 Fc區域具有序列編號:7的胺基酸序列,而該DcR3蛋白包含一由序列編號:5所組成之N端胜肽、一由序列編號:4所組成之HBD胜肽,以及一由序列編號:6所組成的C端胜肽,其中該N端及C端胜肽是分別位於及連接於由序列編號:4所組成之胜肽的上游及下游。
如同上述,IAV感染會造成嚴重的組織損傷,包含因大量白血球浸潤所造成的肺部損傷,且通常伴隨著發炎細胞激素的高量表現。因此,本揭示內容的第二態樣是關於一種用以減緩一有需要個體之肺部損傷的方法;具體來說,該肺部損傷是由與IAV感染相關之過量發炎反應所導致。該方法包含對該個體投予一治療有效量之融合蛋白。在一實施例中,該融合蛋白是HBD.Fc,其係包含彼此相互連結之一由序列編號:4所組成的HBD胜肽,及一由序列編號:7所組成的人類IgG1 Fc區域。在另一實施例中,該融合蛋白是DcR3.Fc,其係包含彼此相互連結之一DcR3蛋白及一人類IgG1 Fc區域;該人類IgG1 Fc區域具有序列編唬:7的胺基酸序列,而該DcR3蛋白則包含一由序列編號:5所組成之N端胜肽、一由序列編號:4所組成之HBD胜肽,以及一由序列編號:6所組成的C端胜肽,其中該N端及C端胜肽是分別位於及連接於由序列編號:4所組成之胜肽的上游及下游。
依據本揭示內容一實施方式,本發明方法可用以治療或預防IAV感染及/或與IAV感染相關之病徵(例如肺部損傷),其中該IAV可以是H1N1、H2N2、H3N2、H5N1、H7N7、H1N2、H9N2、H7N2、H7N3、H10N7或H7N9。在一較佳的實施例中,該IAV是H1N1。
依據本揭示內容的實施方式,本揭示內容之融合蛋白的治療有效量每劑約為每公斤體重0.5到5毫克。舉例來說,該劑量可以是每公斤個體體重0.5、0.6、0.7、0.8、0.9、1.0、1.5、2.0、2.5、3.0、3.5、4.0、4.5或5.0毫克。在一較佳實施例中,本揭示內容之融合蛋白的治療有效量每劑約為每公斤個體體重0.8到1毫克。為對個體產生一治療功效,融合蛋白於一完整療程中的總投予劑量約為每公斤個體體重1到10毫克;較佳的情況是,總投予劑量約為每公斤個體體重1.6到2毫克。
在本揭示內容之方法中,融合蛋白可由口服、腸內、鼻腔、局部、穿透黏膜或非口服方式投予至該個體,其中非口服方式可以是肌肉注射、靜脈注射或腹腔注射。在本揭示內容一特定實施方式中,是將融合蛋白以靜脈注射方式投予至個體。
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。實施例
材料及方法
細胞培養
將購買自Invitrogen. Inc的FreeStyle 293-F細胞培養於FreeStyle 293表現細胞培養液(FreeStyle 293 Expression Medium, Invitrogen)中,並置於包含8% CO2
潮溼環境之37˚C細胞培養箱、轉速為135 rpm的軌道式搖動器(orbital shaker)平台上培養。將Sf21細胞培養於包含10%經熱去活化之胎牛血清(fetal bovine serum, FBS)的TNM-FH細胞培養液中,並放置於37°C、5% CO2
的環境中生長。
動物
本實驗是使用8到12週大的野生型C57BL/6 (NLAC)小鼠及DcR3基因轉殖小鼠(自行飼育且具有C57BL/6的背景)。DcR3基因轉殖小鼠會持續表現DcR3,且可以血清ELISA確認其表現量。依據Tai等人所述之方法(“Decoy receptor 3 enhances tumor progression via induction of tumor-associated macrophages”,Journal of Immunology
2012, 188, p2464-2471)取得DcR3基因轉殖小鼠。所有的動物皆飼養於國立陽明大學動物中心。本研究所有的實驗流程皆是在國立陽明大學動物飼育及福利委員會(institutional animal care and welfare committee)許可下進行。
載體建構
為建構用以表現融合蛋白 DcR3.Fc的質體pBacPAK9-DcR3.Fc,先利用序列編號:8的正向引子及序列編號:9的反向引子以RT-PCR方式分離人類DcR3
基因的開放閱讀框架(open reading frame)。將放大的產物以同閱讀框架方式建構於包含人類IgG1 Fc之cDNA且經Eco
RI切割之pUC19-IgG1-Fc載體中。之後再將融合基因次轉殖至pBacPAK9載體(Clontech Laboratories, Palo Alto, CA)以產生質體pBacPAK9-DcR3.Fc。在建構用以表現融合蛋白 HBD.Fc (對應於DcR3之GAG結合模組(motif))之質體pcDNA3-HBD.Fc時,先將序列編號:10及11的互補寡核苷酸結合以產生一dsDNA片段,再利用T4多核苷酸激酶(New England Biolabs)對5-羥基末端進行磷酸化反應。將磷酸化後之DNA片段次轉殖至經HincII切割的pBluescript II KS,再以HindIII進行切割,之後以同閱讀框架方式建構至經HindIII切割之pFlag-CMV1 (Sigma-Aldrich)中。以PCR放大具有Flag標記之DcR3_HBD,再將放大片段以同閱讀框架方式與pcDNA3之hIgG1的Fc部分連結,以製得質體pcDNA3-HBD.Fc。
製備融合蛋白
為製備融合蛋白 DcR3.Fc,將質體pBacPAK9-DcR3.Fc與直鏈BacPAK6 DNA (Clontech Laboratories)轉染至Sf21細胞中以產生重組病毒,其係包含DcR3及人類IgG1 Fc區域的基因,且可於Sf21細胞中進行複製。利用該重組病毒感染Sf21細胞,在病毒複製的過程中會產生大量的融合蛋白。由經病毒感染之Sf21細胞的上清液收集融合蛋白,再以蛋白-A瓊脂糖磁珠(protein-A Sepharose bead, Amersham Biosciences)進行純化,並利用 0.1 M甘胺酸緩衝液(pH 3.0)沖提後,以生理食鹽水進行透析。
在製備融合蛋白HBD.Fc時,是依據使用操作指示將質體pcDNA3-HBD.Fc轉染至FreeStyle 293-F細胞中。收集經轉染後之細胞的細胞培養液,與蛋白-A瓊脂糖磁珠作用反應,以0.1 M甘胺酸緩衝液(pH 3.0)沖提結合的蛋白,再以生理食鹽水進行透析。
以
IAV
感染小鼠
用以感染小鼠的IAV (A/Puerto Rico/8/34, H1N1; PR/8)是依標準流程培養於Madin-Darby犬腎臟細胞(Madin-Darby canine kidney cell, MDCK, ATCC®CCL-34™)。將經感染之細胞的上清液儲存於-80°C,利用於MDCK細胞進行的病毒斑試驗(plaque assay)來檢測病毒的力價(titer)。
在以鼻腔吸入方式投予104
PFU (溶於20微升之生理食鹽水)前,先以腹腔注射方式投予小鼠戊巴比妥鈉(sodium pentobarbital)。感染4天後,以聚乙烯管插入氣管,再以總體積為3毫升的生理食鹽水沖洗3次。約可回收2.5毫升的沖洗液;離心後,利用血球計數器計算回收液中的細胞數量,或是以ELISA分析上清液中細胞激素的表現量。以眼後採血(retro orbital bleeding)收集周邊血後,取得小鼠的血清,同時摘取經犠牲之小鼠的肺臟組織,先以10%甲醛固定後,以石蠟包埋組織,再以5毫米的厚度進行切片,利用抗-DcR3抗體(3H5)進行免疫組織化學分析。為測定融合蛋白的保護功效,使野生型C57BL/6小鼠(10-12週大)鼻腔吸入IAV (5 × 103
PFU)後,於第0天及第3天分別以尾靜脈注入方式投予IgG1 (每隻小鼠20微克)、DcR3.Fc (每隻小鼠20微克)或HBD.Fc (每隻小鼠20微克)。每天或至少每二天監測一次小鼠之體重變化及其存活狀況。
以
ELISA
測量細胞激素的表現量
依據使用操作指示,利用ELISA套組(R&D Systems)來分別測量小鼠血清及BALF中,DcR3、TNF-α、IL-1β、IL-6、IFN-α及MCP-1的含量。在進行ELISA分析前,所有的檢體皆係儲存於-80°C的環境中。
流式細胞儀分析
以與螢光接合之抗體(BD Biosciences)對取自BALF的細胞進行染色。抗體分別為:與別藻藍蛋白(allophycocyanin)接合之抗-小鼠F4/80、CD8及NK1.1抗體;與FITC接合之抗-小鼠CD4、B220及GR1抗體。利用FACSCalibur™流式細胞儀(BD Biosciences)來分析染色的細胞,再以CellQuest™軟體(Becton Dickinson)分析結果。
統計分析
以平均值±平均標準差(standard error of mean, S.E.M.)來表示各實驗數值。以Prism套裝軟體(GraphPad Version 5.00)之Studentt
test分析所有實驗結果;若雙尾(2-tailed)p
值< .05,則代表具有統計差異。
實施例
1 DcR3
基因轉殖小鼠可抑制由
IAV
所引發的發炎反應
本實施例是利用由CD68啟動子趨動的DcR3基因轉殖(DcR3-Tg)小鼠來評估DcR3蛋白對IAV感染及與IAV感染相關之病徵的保護功效;野生型(wild-type, WT)小鼠的基因組由於不包含DcR3
基因,因此在本實驗是作為對照組。分別對二組小鼠以鼻腔吸入的方式投予IAV;之後,持續監測支氣管肺泡沖洗液(bronchoalveolar lavage fluid, BALF)中細胞浸潤數量及細胞激素的表現量,直到感染後第7天。第1到4圖分別闡述該些實驗結果。
如第1A圖所示,不論是對照感染 (mock-infected)或是以IAV感染的野生型小鼠(第1A圖分別標記為野生型/對照組及野生型/PR/8)皆不會表現DcR3蛋白。相較之下,可在DcR3基因轉殖小鼠之肺部骨髓細胞(pulmonary myeloid cell)、血清及BALF中偵測到DcR3的表現;且IAV感染會進一步增加其表現量(第1A-1C圖)。在感染後第4天(day 4 post infection, 4 dpi)可觀察到浸潤至肺部的總細胞(第2A圖)及Gr1中
F4/80+
(Gr1int
F4/80+
)巨噬細胞(第2B圖)數量會顯著減少,該些細胞會在感染後7天回復到與野生型小鼠相當的數量;而浸潤至肺部的嗜中性球(neutrophil,第2C圖)、CD4+
T細胞(第2D圖)、CD8+
T細胞(第2E圖)、B細胞(第2F圖)或NK細胞(第2G圖)數量則與對照組小鼠的浸潤數量相當。此外,於感染後第4天亦可觀察到TNF-α (第3A圖)、IL-6 (第3B圖)、IL-1β (第3C圖)、IFN-α (第3D圖)及MCP-1 (第3E圖)的分泌量會顯著下降。相較於野生型小鼠,DcR3基因轉殖小鼠自感染後第8天起體重會較為快速地復原(第4A圖)。此外,DcR3基因轉殖小鼠的存活百分比亦高於野生型小鼠的存活百分比(50%與22%,p
= .042,第4B圖)。
該些結果指出,DcR3可有效抑制由IAV所引發的發炎反應,例如發炎細胞激素的分泌及發炎細胞(特別是巨噬細胞)浸潤至肺臟組織;據此,DcR3可提供有效的保護,使個體免於罹患由IAV造成之會危及生命的病狀。
實施例
2
以
DcR3
融合蛋白抑制由
IAV
所引發的發炎反應
為進一步了解DcR3於對抗IAV感染時的保護功效,以鼻腔吸入方式對野生型小鼠投予IAV,並於第0天及第3天以靜脈注射方式分別投予IgG1、DcR3.Fc或HBD.Fc,其中IgG1是作為對照組。如第5A圖所示,投予IgG1之小鼠的體重減少趨勢會與第4A圖所述之野生型小鼠相同。相較之下,遭受IAV感染後,投予融合蛋白 DcR3.Fc或HBD.Fc之小鼠的體重則會較為穩定(第5A圖)。此外,投予DcR3.Fc或HBD.Fc的小鼠亦較投予IgG1的小鼠擁有較高的存活時間(100%與62.5%,p
= .0277,第5B圖)。
該些結果指出融合蛋白DcR3.Fc或HBD.Fc可減緩與IAV感染相關的病徵,並保護個體免於遭受IAV感染。
總結上述,本揭示內容提供了一種藉由抑制IAV引發之發炎反應來治療或預防IAV感染的方法,其中該發炎反應往往會危害個體的健康,甚至性命。本揭示內容之DcR3.Fc及HBD.Fc皆可抑制IAV引發之肺部發炎反應,進而對遭受IAV感染之個體提供治療及/或保護之功效。
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。
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1A-1C是依據本揭示內容實施例1所繪示之組織化學染色(histochemiscal staining)及酵素免疫吸附法(enzyme-linked immunosorbent assay, ELISA)結果,分別闡述在野生型(wild-type, WT)及DcR3基因轉殖(DcR3-Tg)小鼠中,DcR3於肺臟組織(第1A圖)、血清(第1B圖)及支氣管肺泡沖洗液(bronchoalveolar lavage fluid,BALF,第1C圖)的表現; 第2A-2G圖是依據本揭示內容實施例1所繪示之ELISA結果,分別闡述在取自野生型及DcR3基因轉殖小鼠之BALF中,總細胞(第2A圖)、巨噬細胞(第2B圖)、嗜中性球(neutrophil,第2C圖)、CD4+
T細胞(第2D圖)、CD8+
T細胞(第2E圖)、B細胞(第2F圖)或NK細胞(第2G圖)的細胞數量; 第3A-3E圖是依據本揭示內容實施例1所繪示之ELISA結果,分別闡述在取自野生型及DcR3基因轉殖小鼠之BALF中,腫瘤壞死因子-α (tumor necrosis factor-alpha,TNF-α,第3A圖)、介白素-6 (interleukin-6,IL-6,第3B圖)、IL-1β (第3C圖)、干擾素-α (interferon-alpha,IFN-α,第3D圖)或單核球化學趨化蛋白-1 (monocyte chemoattractant protein-1,MCP-1第3E圖)的表現; 第4A-4B圖是依據本揭示內容實施例1所繪示之折線圖,分別闡述野生型及DcR3基因轉殖小鼠的體重(第4A圖)及存活百分比(第4B圖),其中是先以IAV分別感染該些小鼠後,再連續監測14天以了解其體重變化;以及 第5A-5B圖依據本揭示內容實施例2所繪示之折線圖,分別闡述野生型小鼠的體重(第5A圖)及存活百分比(第5B圖),其中是先以IAV分別感染該些小鼠後,分別投予IgG1、DcR3.Fc及HBD.Fc進行治療;感染後,連續監測14天以了解其體重變化。
根據慣常的作業方式,圖中各種特徵與元件並未依比例繪製,其繪製方式是為了以最佳的方式呈現與本發明相關的具體特徵與元件。
<110> 中央研究院 <120> 一種用以治療A型流感病毒感染的方法 <130> P2847-TW <160> 11 <170> BiSSAP 1.3 <210> 1 <211> 21 <212> DNA <213> 人工序列 <220> <223> HBD 多核苷酸 <400> 1 ctgaagctgc gtcggcggct c 21 <210> 2 <211> 900 <212> DNA <213> 人工序列 <220> <223> DcR3 多核苷酸 <400> 2 atgagggcgc tggaggggcc aggcctgtcg ctgctgtgcc tggtgttggc gctgcctgcc 60 ctgctgccgg tgccggctgt acgcggagtg gcagaaacac ccacctaccc ctggcgggac 120 gcagagacag gggagcggct ggtgtgcgcc cagtgccccc caggcacctt tgtgcagcgg 180 ccgtgccgcc gagacagccc cacgacgtgt ggcccgtgtc caccgcgcca ctacacgcag 240 ttctggaact acctggagcg ctgccgctac tgcaacgtcc tctgcgggga gcgtgaggag 300 gaggcacggg cttgccacgc cacccacaac cgtgcctgcc gctgccgcac cggcttcttc 360 gcgcacgctg gtttctgctt ggagcacgca tcgtgtccac ctggtgccgg cgtgattgcc 420 ccgggcaccc ccagccagaa cacgcagtgc cagccgtgcc ccccaggcac cttctcagcc 480 agcagctcca gctcagagca gtgccagccc caccgcaact gcacggccct gggcctggcc 540 ctcaatgtgc caggctcttc ctcccatgac accctgtgca ccagctgcac tggcttcccc 600 ctcagcacca gggtaccagg agctgaggag tgtgagcgtg ccgtcatcga ctttgtggct 660 ttccaggaca tctccatcaa gaggctgcag cggctgctgc aggccctcga ggccccggag 720 ggctggggtc cgacaccaag ggcgggccgc gcggccttgc agctgaagct gcgtcggcgg 780 ctcacggagc tcctgggggc gcaggacggg gcgctgctgg tgcggctgct gcaggcgctg 840 cgcgtggcca ggatgcccgg gctggagcgg agcgtccgtg agcgcttcct ccctgtgcac 900 <210> 3 <211> 684 <212> DNA <213> 人工序列 <220> <223> hIgG1.Fc 多核苷酸 <400> 3 gacaaaactc acacatgccc accgtgccca gcacccgaac tcctgggggg accgtcagtc 60 ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcaca 120 tgcgtggtgg tggacgtgag ccacgaagac cctgaggtca agttcaactg gtacgtggac 180 ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagtacaa cagcacgtac 240 cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaatggcaa ggagtacaag 300 tgcaaggtct ccaacaaagc cctcccagcc cccatcgaga aaaccatctc caaagccaaa 360 gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggatga gctgaccaag 420 aaccaggtca gcctgacctg cctggtcaaa ggcttctatc ccagcgacat cgccgtggag 480 tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 540 gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 600 aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 660 ctctccctgt ctccgggtaa atag 684 <210> 4 <211> 7 <212> PRT <213> 人工序列 <220> <223> HBD 胜肽 <400> 4 Leu Lys Leu Arg Arg Arg Leu 1 5 <210> 5 <211> 254 <212> PRT <213> 人工序列 <220> <223> DcR3-HBD 胜肽 <400> 5 Met Arg Ala Leu Glu Gly Pro Gly Leu Ser Leu Leu Cys Leu Val Leu 1 5 10 15 Ala Leu Pro Ala Leu Leu Pro Val Pro Ala Val Arg Gly Val Ala Glu 20 25 30 Thr Pro Thr Tyr Pro Trp Arg Asp Ala Glu Thr Gly Glu Arg Leu Val 35 40 45 Cys Ala Gln Cys Pro Pro Gly Thr Phe Val Gln Arg Pro Cys Arg Arg 50 55 60 Asp Ser Pro Thr Thr Cys Gly Pro Cys Pro Pro Arg His Tyr Thr Gln 65 70 75 80 Phe Trp Asn Tyr Leu Glu Arg Cys Arg Tyr Cys Asn Val Leu Cys Gly 85 90 95 Glu Arg Glu Glu Glu Ala Arg Ala Cys His Ala Thr His Asn Arg Ala 100 105 110 Cys Arg Cys Arg Thr Gly Phe Phe Ala His Ala Gly Phe Cys Leu Glu 115 120 125 His Ala Ser Cys Pro Pro Gly Ala Gly Val Ile Ala Pro Gly Thr Pro 130 135 140 Ser Gln Asn Thr Gln Cys Gln Pro Cys Pro Pro Gly Thr Phe Ser Ala 145 150 155 160 Ser Ser Ser Ser Ser Glu Gln Cys Gln Pro His Arg Asn Cys Thr Ala 165 170 175 Leu Gly Leu Ala Leu Asn Val Pro Gly Ser Ser Ser His Asp Thr Leu 180 185 190 Cys Thr Ser Cys Thr Gly Phe Pro Leu Ser Thr Arg Val Pro Gly Ala 195 200 205 Glu Glu Cys Glu Arg Ala Val Ile Asp Phe Val Ala Phe Gln Asp Ile 210 215 220 Ser Ile Lys Arg Leu Gln Arg Leu Leu Gln Ala Leu Glu Ala Pro Glu 225 230 235 240 Gly Trp Gly Pro Thr Pro Arg Ala Gly Arg Ala Ala Leu Gln 245 250 <210> 6 <211> 39 <212> PRT <213> 人工序列 <220> <223> HBD-hIgG1.Fc 胜肽 <400> 6 Thr Glu Leu Leu Gly Ala Gln Asp Gly Ala Leu Leu Val Arg Leu Leu 1 5 10 15 Gln Ala Leu Arg Val Ala Arg Met Pro Gly Leu Glu Arg Ser Val Arg 20 25 30 Glu Arg Phe Leu Pro Val His 35 <210> 7 <211> 227 <212> PRT <213> 人工序列 <220> <223> hIgG1.Fc 胜肽 <400> 7 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <210> 8 <211> 26 <212> DNA <213> 人工序列 <220> <223> DcR3 正向引子 <400> 8 ggaattcaag gaccatgagg gcgctg 26 <210> 9 <211> 26 <212> DNA <213> 人工序列 <220> <223> DcR3 反向引子 <400> 9 ggaattcgtg cacagggagg aagcgc 26 <210> 10 <211> 39 <212> DNA <213> 人工序列 <220> <223> 互補序列-1 <400> 10 aagcttgggc tgaagctgcg tcggcggctc gggaagctt 39 <210> 11 <211> 39 <212> DNA <213> 人工序列 <220> <223> 互補序列-2 <400> 11 aagcttcccg agccgccgac gcagcttcag cccaagctt 39
Claims (16)
- 一種融合蛋白之用途,其係用於製備一可於一個體體內治療或預防A型流感病毒感染的藥物,其中該融合蛋白包含一由序列編號:4所組成的第一胜肽及一與該第一胜肽連結之人類IgG1 Fc區域。
- 如請求項1所述之用途,其中該融合蛋白更包含一由序列編號:5所組成的第二胜肽及一由序列編號:6所組成的第三胜肽,其中該第二及第三胜肽分別位於及連接於該由序列編號:4所組成之第一胜肽的上游及下游。
- 如請求項1所述之用途,其中該藥物是以每劑約為每公斤體重0.5到5毫克的治療有效量投予該個體。
- 如請求項3所述之用途,其中該藥物是以每劑約為每公斤體重0.8到1毫克的治療有效量投予該個體。
- 如請求項1所述之用途,其中在一完整療程中該藥物是以約為每公斤體重1到10毫克的治療有效量投予該個體。
- 如請求項5所述之用途,其中在一完整療程中該藥物是以約為每公斤體重1.6到2毫克的治療有效量投予該個體。
- 如請求項1所述之用途,其中該融合蛋白是由口服、腸內、鼻腔、局部、穿透黏膜或非口服方式投予至該個體。
- 如請求項7所述之用途,其中該非口服方式可以是肌肉注射、靜脈注射或腹腔注射。
- 一種融合蛋白之用途,其係用於製備一可減緩一有需要個體之肺部損傷的藥物,其中該肺部損傷是由與A型流感病毒感染相關之過量發炎反應所造成的;以及該融合蛋白包含一由序列編號:4所組成的第一胜肽及一與該第一胜肽連結之人類IgG1 Fc區域。
- 如請求項9所述之用途,其中該融合蛋白更包含一由序列編號:5所組成的第二胜肽及一由序列編號:6所組成的第三胜肽,其中該第二及第三胜肽分別位於及連接於該由序列編號:4所組成之第一胜肽的上游及下游。
- 如請求項9所述之用途,其中該藥物是以每劑約為每公斤體重0.5到5毫克的治療有效量投予該個體。
- 如請求項11所述之用途,其中該藥物是以每劑約為每公斤體重0.8到1毫克的治療有效量投予該個體。
- 如請求項9所述之用途,其中在一完整療程中該藥物是以約為每公斤體重1到10毫克的治療有效量投予該個體。
- 如請求項13所述之用途,其中在一完整療程中該藥物是以約為每公斤體重1.6到2毫克的治療有效量投予該個體。
- 如請求項9所述之用途,其中該融合蛋白是由口服、腸內、鼻腔、局部、穿透黏膜或非口服方式投予至該個體。
- 如請求項15所述之用途,其中該非口服方式可以是肌肉注射、靜脈注射或腹腔注射。
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徐湘婷, 第三號誘餌受體所調控之第二型巨噬細胞於流行性感冒病毒感染中所扮演的角色 國立陽明大學生命科學院微生物暨免疫學研究所碩士論文 國圖上架日: 2011/4/26 * |
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