TWI496888B - 免疫抑制相關疾病之治療 - Google Patents
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Description
本發明係有關於細胞增生疾病及免疫不全症之治療方法。
免疫系統可使一生物體抵禦病原菌感染、細胞轉型(cellular transformation)以及物理或化學性傷害。一旦免疫系統較平常不活化，會發生免疫不全(immunodeficiency)或免疫抑制(immunosuppression)而導致危急生命之感染或癌症的發生。免疫抑制可能由疾病所造成，或由藥物，或感染所產生。已知系統性免疫抑制與不正常之骨髓形成(myelopoiesis)及繼發之腫瘤生長、骨髓抑制(myelosuppressive)療法、及生長因子的使用和隨後之骨髓衍生免疫抑制細胞的擴增/調動有關。該骨髓衍生抑制細胞(MDSCs，myeloid-derived suppressor cells)藉由多種機制以減少活化之T細胞之數量，以及抑制T細胞之功能，因此導致免疫抑制及耐受性(tolerance)。因此，MDSCs具有原腫瘤(pro-tumor)之角色。此外，MDSCs具有多效活性(pleiotropic activities)，其包含可於腫瘤微環境中誘導突變、促進血管新生作用(angiogenesis)及轉移(metastasis)，以及直接支持腫瘤生長及發炎反應。實際上，該等細胞於多種病理情況中係會增加，包含感染、炎症、移植物抗宿主疾病(graft-versus-host disease)、創傷壓力、及腫瘤疾病(Dolcettiet al
.,Cancer Lett. 2008 Aug 28;267(2):216-25;Talmadge,Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5243-8)。
本發明至少部份係基於非預期地自成熟或年輕動物中發現一幹細胞群，似胚葉細胞-幹細胞群(BLSCs，blastomere-like stem cells)，其可顯著地降低動物體內之MDSCs的數量。
因此，本發明一方面之特徵在於一種治療患者中細胞增生疾病之方法。該方法包含將有效量之BLSCs投予有需要之個體。
細胞增生疾病係指一疾病具有不受控制之自發性細胞生長(包含惡性及非惡性生長)，以及受MDSCs調節免疫抑制作用之特徵。該疾病之例子包含大腸癌、乳癌、前列腺癌、肝癌、黑色素瘤、肺癌、神經膠母細胞瘤、腦瘤、造血性惡性腫瘤、視網膜胚細胞瘤(retinoblastoma)、腎細胞癌、頭部或頸部癌、子宮頸癌、胰臟癌、食道癌、卵巢癌，及鱗狀上皮細胞瘤。
在本文中「個體」乙詞係指人類或非人類之動物。非人類之動物的例子包含所有具有免疫系統之脊椎動物，如：哺乳類動物，包括非人類之靈長類(特別係指高等靈長類)、狗、齧齒動物(如小鼠或大鼠)、天竺鼠、貓、農場動物(如馬、牛、羊或豬)，以及非哺乳類動物，包括鳥類、兩棲動物、爬蟲類等。在一較佳具體實施例中，該個體為人類。在另一具體實施例中，該個體係為試驗動物或適用於疾病模式之動物。
待治療之患有細胞增生疾病之個體，可由針對該疾病之標準診斷技術來鑑定。在本文中「治療」乙詞係指將組成物(例如細胞組合物)投予罹患細胞增生疾病或有發展成細胞增生疾病之風險的個體，其目的為對於該疾病、該疾病之症狀、衍生自該疾病之症狀或傾向損傷/疾病之體質加以治癒、減輕、解除、治療、延遲其發生、預防或緩解。在本文中「有效量」乙詞係指能使被治療之個體產生預期之醫療結果之組合物的量。該治療方法可單獨進行或與其他藥物或療法併行。
本發明之特徵亦在於一種減少個體內MDSCs數量的方法，其藉由將有效量之BLSCs投予有需要之個體。
本發明另一方面之特徵為一種克服個體內免疫抑制作用之方法。該方法包含將有效量之BLSCs投予有需要之個體。該免疫抑制作用係為由MDSCs調節之免疫抑制作用。在又另一方面，本發明之特徵在於一種調節個體內免疫反應之方法。該方法包含將有效量之BLSCs投予有需要之個體。
於前述之每一種方法中，該個體可為具有細胞增生疾病、感染或免疫不全疾病之患者。於每個方法中，該BLSCs以每次1 x 108
至1 x 1011
之量投予該患者，較佳為每次5 x 108
至5 x 1010
，或更佳為每次1 x 109
至1 x 1010
。為了減少或避免宿主排斥反應，該等細胞較佳者為自該個體自體衍生者。該BLSCs可為每兩週投予2至5次，或更佳者，為每兩週投予3次。該個體可視需要於投予該BLSCs前先檢測MDSCs之數量。若一來自該個體的樣本，其MDSCs數量係統計上高於來自正常受試者之樣本，則該個體係為前述方法之治療候選。該個體亦可於投予該BLSCs後檢測MDSCs之數量，以確認投予該BLSCs之效用。例如：若經投予後該MDSCs之數量統計上低於投予前者，則該BLSCs之投予治療係為有效。
本發明之一或多個具體實施例之細節係闡述於後文中。本發明之其他特徵、目的以及優點可藉由說明書內容及申請專利範圍得以清晰明瞭。
本發明係關於使用BLSCs調節免疫反應及治療相關疾病，例如細胞增生疾病及其他免疫不全症。
BLSCs為在成年或年輕動物中之一群非胚胎幹細胞。此等細胞為全能性且具有與胚胎幹細胞相似之分化能力。參見WO2007/100845。BLSCs包含正常之整套染色體，且BLSCs為細胞譜系未定(lineage-uncommitted)，且可形成體內所有體(非生殖)細胞。它們可分化為各種細胞譜系，其包含衍生自外胚層(如：神經元、星狀膠細胞、寡樹突神經膠細胞(oligodendrocytes)及角質細胞(keratinocytes))、中胚層(如：骨骼肌、平滑肌、心肌、脂肪組織、軟骨、骨、真皮、血液細胞、韌帶組織(ligament tissue)、肌腱及內皮細胞)及內胚層(如：GI上皮細胞、肝細胞、卵細胞、膽細胞、胰細胞(如α細胞、β細胞及γ細胞)及管道細胞(ductal cells))之細胞。此外，BLSCs可分化為精原細胞(spermatogonia)及形成生殖配子精子及/或卵子，及胚胎組織和細胞，以及胎盤之胎兒部分。該細胞易對於譜系誘導劑、增生劑及分化抑制劑產生反應。另一方面，該等細胞對於發展劑(progression agents)較無反應。與似外胚層幹細胞(epiblast-like stem cells)相同，BLSCs於細胞培養至長滿時並無接觸抑制作用，但只要該細胞被維持於適當之營養供給時，則會形成多層融合之細胞層。BLSCs不會表現代表前驅或分化細胞、胚層譜系幹細胞、或似外胚層幹細胞之表型表現標記。相反地，BLSCs表現一般及特定的胚胎譜系標記，例如：胚胎幹細胞標記CD66e、HCEA、CEA以及CEA-CAM-1。BLSCs於成熟組織中常為靜態。然而，當上述組織受到傷害時，BLSCs便會活化及分化以修復該受損之組織。
BLSCs可藉由下述之實施例1或專利申請號WO2007/100845所述之方法來製備。一般而言，該細胞可自成年或年輕動物之多種組織中分離出來，包含血液、骨髓及骨骼肌。為了確認所分離之細胞確實為BLSCs，試驗者可檢驗一些特徵，包含(1)懸浮之細胞尺寸，其小於1微米；(2)細胞表面標記，如CD66e+
；以及(3)台盼藍染色呈陽性。細胞表面標記之抗體，如CD66e可被使用於鑑定BLSCs。為此目的，適當的抗體可與適當之標記結合，如：螢光異硫氰酸鹽(FITC，fluorescein isothiocyanate)、藻紅蛋白(PE，phycoerythrin)、別藻藍蛋白(APC，allophycocyanin)或量子點(quantum dots)。BLSCs可進一步使用該類抗體並以流式細胞儀來富集。
該富集之細胞群接著以標準技術來測試。為了確認該細胞之分化潛力，該細胞可藉由習知技藝方法被誘導以形成，例如：神經元-神經膠質細胞、骨細胞以及脂肪細胞。例如，該細胞可被繼代及培養至長滿(confluence)，移轉至骨生成培養基或脂肪生成培養基，並培養一段適當時間(如：三週)。請參閱如：美國專利第7470537號、第7374937號及第6777231號。骨生成分化能力可藉由鈣累積之礦化作用來評估，該礦化作用可藉由von Kossa染色法觀察。藉由油紅O將細胞內油滴染色，並於顯微鏡下觀察以檢測脂肪生成分化情形。對於神經分化方面，該細胞可於神經生成培養基中培養適當時間(如七天)，接著將其以無血清(serum depletion)之環境處理，並與β-巰基乙醇(β-mercaptoethanol)培養。請參閱美國專利第7470537號及美國專利申請案第20080274087號、第20080213228號及第20080152629號。經分化後，該細胞呈現折光細胞體型態(refractile cell body)，及具有延伸的似軸突結構並構成網絡。以譜系特異性標記進行免疫細胞化學染色即可進一步確認神經之分化情形。該標記之例子包含神經元特異性第三類β-微管蛋白(Tuj-1)、神經絲狀結構蛋白(neurofilament)以及GFAP。
另外，可藉由BLSCs不具接觸抑制作用(contact inhibition)之特點，以確認該等分離細胞之身份。為此，可將該分離細胞培養至長滿。於此條件下，BLSCs可形成球狀細胞聚體、細胞均佈之多層結構(multiple confluent layers)、或網孔(mesh-net)結構。相反的，CD42+
細胞或血小板無法形成前述結構，如細胞聚體。
經該等確認後之BLSCs可進一步於一非分化性之培養基中以超過10、20、50、100或300代以上之細胞倍增率(population doubling)來培養增殖，且其中無自發性分化、老化、型態改變、生長速度增加、或改變為具能力分化為神經元之跡象。該等細胞可於使用前以標準方法來保存。如本文所述，BLSCs可被用以降低個體內之MDSCs的數量。
此處所使用的「MDSCs」乙詞係指自骨髓衍生的、異質的細胞群，其包含骨髓單核細胞性分化之連續性階段。此等異質性係可藉由複雜的表面標記(surface marker)表現模式來反映。鼠類MDSCs的主要表現型係可由下述標記來界定：CD11b+
、Gr-1+
、F4/80int
、CD11clow
、MHCII-/low
、Ly-6C+
、ER-MP58+
、CD31+
以及IL-4Rα+
。人類MDSCs為未成熟之表現型，包含譜系陰性(Lin-
，lineage negative)、CD14-
、人類白血球抗原DR-陰性(HLA-DR-
，human leukocyte antigen DR-negative)、CD15+
、CD34+
、CD11b+
、CD33+
、以及CD13+
(Dolcettiet al
.,Cancer Lett. 2008 Aug 28;267(2):216-25;Talmadge,Clin Cancer Res. 2007 Sep 15;13(18 Pt l):5243-8)。
帶有腫瘤之動物及癌症患者的骨髓形成(myelopoiesis)存在缺陷，此將導致MDSCs的累積。腫瘤成長的期間，於主要發炎類型中，MDSCs不論在局部性或系統性皆會被吸引且幫助腫瘤的成長。該等細胞會維持腫瘤成長並提供有利於轉型細胞(transformed cells)增生、產生新突變、擴增及規避宿主之免疫監督(immunosurveillance)的微環境；此外，MDSCs會參與腫瘤血管新生(neoangiogenesis)。
因此，BLSCs所調節之MIDSCs抑制作用，係可用於治療癌症及其他細胞增生疾病。尤其是，其可被用於治療具有不正常高量MSDC之疾病。此處所使用的「癌症」乙詞係指特徵為無法控制細胞生長、侵入和具有轉移之可能性之疾病。癌細胞具自發性生長之能力，例如：不正常地快速細胞生長。該詞意欲包含所有類型之癌化生長或致癌過程、轉移組織或惡性轉型細胞、組織或器官，不論組織病理類型或侵入階段。癌症之範例包含，但不限於，癌及肉瘤，如：白血病、肉瘤、骨肉瘤、淋巴瘤、黑色素瘤、神經膠質瘤、嗜鉻性細胞瘤、肝癌、卵巢癌、皮膚癌、睪丸癌、胃癌、胰臟癌、腎癌、乳癌、前列腺癌、大腸癌、頭部或頸部癌、腦癌、食道癌、膀胱癌、腎臟皮質癌、肺癌、支氣管癌、子宮內膜癌、鼻咽癌、子宮頸癌或肝癌、及其他原發部位不明之癌症。
MDSCs已於病理學中被揭示，但未被揭示在腫瘤中，其參與了發炎免疫反應，如超級抗原刺激(super-antigen stimulation)及感染，如睡眠蟲(trypanosomiasis)、沙門氏桿菌(salmonellosis)及念珠菌(candidiasis)。例如：MDSCs數量之增加被發現與發炎、感染及移植體對抗宿主疾病有關，且會抑制活躍或新的T細胞反應(Talmadge,Clin Cancer Res. 2007 Sep 15;13(18 Pt 1):5243-8)。MDSCs已顯示可誘導免疫抑制狀態，其係藉由降低活化之T細胞數量及藉由多種機制抑制T細胞功能，該等機制包含藉由精胺酸酶-1(arginase-1，ARG1)以耗盡左旋精胺酸(L-arginine)，以及藉由誘導性一氧化氮合成酶(inducible nitric oxide synthase)產生一氧化氮、活性氧化物，和活化之氮氧化物。因此，BLSCs所調節之MDSCs抑制作用亦可能用於讓MDSCs消除之開發中的策略，以治療移植體對抗宿主疾病、發炎及自體免疫疾病，而不僅是用於治療腫瘤。
本發明之範疇係為一種用以治療個體中MDSCs導致之免疫不全症，舒緩該疾病的症狀，或延遲該疾病之發生。該疾病之一示例係為細胞增生性疾病。可藉由標準技術來診斷其狀況或疾病以鑑定出需被治療之個體。尤其是，若該個體體內之MDSCs數量係統計上高於同一個體先前之MDSC數量時，或高於一正常個體時，可認定為需治療之個體。該治療方法需將有效量之前述BLSCs投予至一需治療之個體。
因此，本發明提供含有BLSCs之醫藥組合物。該等醫藥組合物可藉由混合一治療有效量之BLSCs，及視需要之其他活性物質，及一醫藥可接受的載劑來製備。該載劑可依據投予路徑具有不同形式。其他活性物質之例子包含可抑制MDSCs之免疫抑制活性、干擾MDSCs之聚集，或改善身體免疫功能之化合物。
前述醫藥組合物可藉由常規的醫藥賦形劑及製備方法以製備。所有賦形劑皆可與崩解劑、溶劑、粒化劑、保濕劑及黏合劑進行混合。本文所述之「有效量」或「治療有效量」乙詞係指可使得特定疾病之至少一症狀或參數得以顯著地改善之數量。BLSCs之治療有效量可由習知方法所決定。用以治療疾病之有效量係可藉由該領域具有通常技藝者以習知試驗方法輕易地決定。而用以投予至個體之確切數量將依照該疾病之情況及嚴重度，以及該個體之生理情況而有所不同。任何症狀或參數之顯著地改善係可由熟諳該技藝者或病患對醫師之報告來決定。將被明瞭的是，前述疾病之任何症狀或參數具任何臨床上或統計上顯著減弱或改善者皆隸屬本發明之範疇內。臨床顯著地減弱或改善意指對於該病患及/或醫師係為顯而易見的。
在本文中「醫藥可接受的」乙詞係指當投予至一人類時，該等組成物中之分子個體及其他成分係為生理上可接受的，且一般不會產生不良反應。較佳地，「醫藥可接受的」乙詞意指係受聯邦監管機關或州政府核准，或列於美國藥典或於其他一般藥典所認可用於哺乳類動物，特別指人類。醫藥可接受鹽類、酯類、醯胺，以及前驅藥係指該些鹽類(如：羧酸鹽、胺基酸添加鹽)、酯類、醯胺，以及前驅藥，於可靠的醫療判斷範疇內，適合使用於與病患組織接觸而無過渡毒性、刺激性、過敏反應等；且需考量該等用途之合理的利益/風險比及有效性。
可應用於前述醫藥組合物之載劑包含稀釋劑、賦形劑或載體，其可與化合物一起被投予。該等醫藥載劑可為無菌的液體，例如水及油。較佳之載劑為水或水溶液、鹽液及液態葡萄糖和甘油溶液，特別可作為注射溶液。適用之醫藥載劑如由E. W. Martin所撰之"Remington's Pharmaceutical Sciences"第18版中所描述。
該等BLSCs可透過注入或注射(例如：靜脈注射、鞘內注射、肌肉注射、腔內注射、氣管內注射、腹腔注射或皮下注射)、口服、皮膚穿透或以其他習知方法投予一個體。於一示例中，該等細胞可被直接注射於一位置或於一組織中(如：肝臟或胰臟)，該處係具有腫瘤或免疫抑制反應發生。投予可為每兩週一次、一週一次或更頻繁，但當該疾病或失調於一穩定階段時，其投予頻率則可以減少。
異源的及自體的BLSCs皆可被使用。於前者情況，HLA之吻合將可避免或降低宿主之反應。於後者情況，自體的BLSCs係從一個體中被純化及增生後進行保存以備用。宿主之BLSCs可於活體外培養在含有宿主細胞或移植T細胞之環境中，並重新被送回該宿主。上述步驟可使BLSCs於該宿主內被視為自體細胞，並較佳地降低T細胞活性。
劑量和投予頻率將取決於臨床症狀，其確認緩解階段之維持，或於急性期之至少一個或多個，較佳為多於一個之該領域熟諳技藝人士所知之臨床症狀被減少或消失。一般而言，劑量和用藥頻率將部分取決於疾病狀況或失調之病理症狀及臨床和亞臨床症狀經前述組成物治療後的削弱情形。如本領域熟諳技藝者所知悉，劑量和投予途徑可依據被治療之病患或哺乳類個體之年齡、性別、身體狀況，以及共軛利益和副作用來調整。
據報告指出，MDSCs於一腫瘤處進行聚集，係可能由多種不同之腫瘤衍生可溶性因子(tumor-derived soluble factors)所觸發，其影響骨髓形成、骨髓細胞調動及其活化甚鉅(Dolcettiet al
.,Cancer Lett.2008 Aug 28；267(2)：216-25)。全能性或多能性幹細胞(如BLSCs)可能干擾MDSCs之活化或遷移或促進MDSCs之分化，以克服MDSCs所調節之免疫抑制作用。
因此，全能性或多能性幹細胞，除了BLSCs外，亦可被用於治療前述具有MDSCs累積之特徵的免疫缺乏疾病。該等全能性或多能性幹細胞之示例包含由上述BLSCs所衍生之細胞，例如SBR細胞及SBT細胞，該等細胞係藉將該BLSCs分別與維生素A酸(RA，retinoic acid)及轉形生長因子β(TGF-β，transforming growth factor beta)共同培養所衍生。該等全能性或多能性幹細胞之示例亦包含胚胎幹細胞(ES細胞，embryonic stem cells)、附著的BLSCs(aBLSCs，adherent BLSCs)、過渡的BLSCs(trBLSCs，transitional BLSCs)，以及似上胚葉幹細胞(ELSCs，epiblast-like stem cells)，如WO2007/100845所述。因此，本發明之範疇為使用該全能性或多能性幹細胞以治療前述之免疫不全症之方法。
治療策略係基於來自於成熟或年輕動物之幹細胞，例如：BLSCs，其擁有許多超越胚胎幹細胞(ES)之優點。首先，藉由
提供良好之標記，BLSCs易於從成熟或年輕動物的組織中取得。第二點，可從血液中取得大量之BLSCs(超過2 x 108
/毫升)。第三點，BLSCs易於被維持及擴增，且可被誘導分化為特定譜系之細胞。第四點，BLSCs一旦注入於一個體體內不會發展為畸胎瘤(teratoma)，因此，亦較ES細胞更為安全。最後同樣重要的是，取得及使用BLSCs不會涉及操作或殺害胚胎，及相關之道德議題。
以下具體之實施例僅供示例說明，非用以限制未於本發明揭示者。無需進一步詳細闡述，咸信本領域熟諳技藝者可基於本文之說明，將本發明發揮至極限。
用於活化、純化及擴增BLSCs之方法係已揭示於專利申請案，申請號為WO/2007/100845。於本實施例中，BLSCs係自人類血液中以兩種方法純化而得，血漿分段法(plasma fraction method)及溶血法(hemolysis method)。
簡言之，血漿分段法係使用標準方法於第一人類個體取得全血樣本(1毫升)。該樣本接著被儲存於4℃約7-9天，再以專利申請案WO/2007/100845所述之方式從該樣本中使BLSCs增生。
該溶血法係以專利申請案WO/2007/100845所述之方式以取得一溶血片段(hemolysis fraction)。簡言之，從第二人類個體中取得約1毫升之全血並儲存於約4℃、含EDTA或其他鈣離子複合劑(Ca2+
complexing agents)之運輸培養基(transport medium)(如：Moraga培養基，其目錄編號：MBC-HUB-MED-100-A004，加州洛杉磯Moraga生技公司)中約9天。9天後，以約50毫升之滅菌後溶血溶液(如：MBC-ASB-REBG-900A-001)將全血樣本中之紅血球進行溶解。經離心後(如：於1800 xg
，10分鐘)，細胞碎片及溶解後細胞被移除，將細胞沈澱物重新懸浮於Moraga滅菌重組
(reconstitution)溶液中(MBC-ASB-REBG-900A-002)。
前述兩種細胞群係使用FITC標記之抗CD10抗體、PE標記之抗CD66e抗體、APC標記之抗CD90抗體，以流式細胞儀進行分析。結果整理於表1中。
如表1所示，當使用溶血法時，約有5.81%、66.67%、及3.11%之分離細胞係分別為BLSCs(CD10-
CD66e+
)、過渡的BLSCs(trBLSCs，CD10+
CD66e+
)及似上胚葉幹細胞(ELSCs，CD10+
CD66e-
)。約有0.62%、13.65%及55.13%之細胞分別為CD10-
CD90+
、CD10+
CD90+
(過渡的似上胚葉幹細胞(trELSCs))，以及CD10+
CD90-
。BLSCs可基於其標記(CD10-
CD66e+
)進一步富化。該方法之產率約200 x 106
BLSCs/毫升血液。
當使用血漿分段法時，約有為9.14%、2.99%及1.10%之分離細胞係分別為BLSCs、過渡的BLSCs及ELSCs。約有9.8%、2.2%及1.46%之細胞係分別為CD10-
CD90+
、CD10+
CD90+
(trELSCs)、CD10+
CD90-。該方法之產率約239 x 106
BLSCs/毫升血漿。
該BLSCs係為台盼藍(trypan blue)染色陽性，且其大小一
般小於1微米，此點不同於血小版(CD42+
且台盼藍染色陰性)。尤其是，與血小板不同的是，血小板缺乏細胞核，且不會增生及分化，而BLSCs可以如專利申請案WO/2007/100845所述之方式於培養基中增生並維持未分化狀態擴增。BLSCs缺乏接觸抑制作用，其可形成球狀之細胞聚體、細胞均佈之多層結構及網孔(mesh-net)結構。該等細胞之聚集將可導引細胞型態變化。相反地，CD42+
細胞或血小板不會形成前述結構，如細胞聚體。
該BLSCs接著以專利申請案WO/2007/100845所述之方法或其他習知方法進行其分化能力之測試。可觀察到的是，於習知誘導條件下，該等細胞可分化為多種細胞譜系，其包含該些源自外胚層、中胚層、內胚層及精原細胞的細胞譜系。該等細胞可維持未分化狀態及擴增超過300代，且不會失去其分化能力。該等細胞不會形成畸胎瘤。
BLSCs係根據上述方法從人類個體中被純化出來，並以1 x 109
細胞量自體投予給同一個體。於投與後第0、14及28天，從該個體採取血液樣本。接著以細胞計數分析法檢測血液中MDSCs及調控T細胞(Treg)之量。可發現到分別於第0、14及28天，MDSCs(CD14-
CD33+
CD11b+
Lin-
)的數量分別佔總周邊血液單核細胞(PBMC，peripheral blood mononuclear cells)之9.24%、2.19%及0.35%。此結果指出BLSCs可顯著地降低於該個體之MDSCs的數量，因此可用以治療具有MDSCs相關免疫不全症之患者。
所有於本說明書所揭露之特徵係可以任何組合方式組合。於本說明書中所揭露之每一特徵可藉由另一相同、等效、或相似目的之可替換特徵來置換。因此，除非明確聲明，否則每一揭露之特徵僅為各種等效或相似特徵的一般系列之示例。
於前述說明中，該領域熟諳技藝者可輕易確認本發明之必要技術特徵，在無脫離其精神及範圍下，可對本發明進行各種不同改變及修改以使其適用於各種不同之用途及情況。因此，其他之具體實施例亦在以下申請專利範圍之範疇內。
Claims (24)
- 一種似胚葉細胞-幹細胞於製造治療個體中細胞增生異常之藥劑之用途，其中該藥劑包含治療有效量的似胚葉細胞-幹細胞。
- 如申請專利範圍第1項之用途，其中該藥劑包含1 x 108 至1 x 1011 的似胚葉細胞-幹細胞。
- 如申請專利範圍第2項之用途，其中該藥劑包含5 x 108 至5 x 1010 的似胚葉細胞-幹細胞。
- 如申請專利範圍第3項之用途，其中該藥劑包含1 x 109 至1 x 1010 的似胚葉細胞-幹細胞。
- 如申請專利範圍第1項之用途，其中該藥劑每兩週投予2至5次。
- 如申請專利範圍第5項之用途，其中該藥劑每兩週投予3次。
- 如申請專利範圍第1項之用途，其中該似胚葉細胞-幹細胞係為自體移殖之似胚葉細胞-幹細胞。
- 如申請專利範圍第1項之用途，於該藥劑投予之前或之後，測定該個體內之骨髓衍生抑制細胞的數量。
- 一種似胚葉細胞-幹細胞於製造減少個體中骨髓衍生抑制細胞數量之藥劑之用途，其中該藥劑包含治療有效量的似胚葉細胞-幹細胞。
- 如申請專利範圍第9項之用途，其中該藥劑包含1 x 108 至1 x 1011 的似胚葉細胞-幹細胞。
- 如申請專利範圍第10項之用途，其中該藥劑包含5 x 108 至5 x 1010 的似胚葉細胞-幹細胞。
- 如申請專利範圍第11項之用途，其中該藥劑包含1 x 109 至1 x 1010 的似胚葉細胞-幹細胞。
- 如申請專利範圍第12項之用途，其中該藥劑每兩週投予2至5次。
- 如申請專利範圍第13項之用途，其中該藥劑每兩週投予3次。
- 如申請專利範圍第9項之用途，其中該似該胚葉細胞-幹細胞係為自體移殖之似該胚葉細胞-幹細胞。
- 如申請專利範圍第9項之用途，於該藥劑投予之前或之後，測定該個體內之骨髓衍生抑制細胞的數量。
- 一種似胚葉細胞-幹細胞於製造克服個體內骨髓衍生抑制細胞介導的免疫抑制作用之藥劑之用途，其中該藥劑包含治療有效量的似胚葉細胞-幹細胞。
- 如申請專利範圍第17項之用途，其中該藥劑包含1 x 108 至1 x 1011 的似胚葉細胞-幹細胞。
- 如申請專利範圍第18項之用途，其中該藥劑包含5 x 108 至5 x 1010 的似胚葉細胞-幹細胞。
- 如申請專利範圍第19項之用途，其中該藥劑包含1 x 109 至1 x 1010 的似胚葉細胞-幹細胞。
- 如申請專利範圍第17項之用途，其中該藥劑每兩週投與2至5次。
- 如申請專利範圍第21項之用途，其中該藥劑每兩週投與3次。
- 如申請專利範圍第17項之用途，其中該似胚葉細胞-幹細胞係為自體移殖之似胚葉細胞-幹細胞。
- 如申請專利範圍第17項之用途，於該藥劑投予之前或之後，測定該個體內之骨髓衍生抑制細胞的數量。
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| TW (1) | TWI496888B (zh) |
| WO (1) | WO2010099044A2 (zh) |
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| US8563307B2 (en) | 2009-02-24 | 2013-10-22 | James Wang | Treatment of immunosuppression-related disorders |
| US8679474B2 (en) | 2010-08-04 | 2014-03-25 | StemBios Technologies, Inc. | Somatic stem cells |
| US8741642B2 (en) | 2010-10-22 | 2014-06-03 | Virginia Commonwealth University | Methods for producing autologous immune cells resistant to myeloid-derived suppressor cells effects |
| TWI571513B (zh) | 2011-09-28 | 2017-02-21 | 幹細胞生物科技股份有限公司 | 體幹細胞及其製備方法 |
| WO2013176785A1 (en) * | 2012-05-21 | 2013-11-28 | The Trustees Of Columbia University In The City Of New York | Trefoil family factor and uses thereof |
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| US9212225B1 (en) | 2014-07-01 | 2015-12-15 | Amphivena Therapeutics, Inc. | Bispecific CD33 and CD3 binding proteins |
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| EP2400971A1 (en) | 2012-01-04 |
| US8563307B2 (en) | 2013-10-22 |
| ES2582582T3 (es) | 2016-09-13 |
| EP2400971A4 (en) | 2013-03-27 |
| JP5809068B2 (ja) | 2015-11-10 |
| WO2010099044A2 (en) | 2010-09-02 |
| US9770473B2 (en) | 2017-09-26 |
| CN102325537A (zh) | 2012-01-18 |
| US20100215622A1 (en) | 2010-08-26 |
| JP2012518646A (ja) | 2012-08-16 |
| EP2400971B1 (en) | 2016-05-18 |
| WO2010099044A9 (en) | 2010-12-16 |
| TW201040278A (en) | 2010-11-16 |
| CN102325537B (zh) | 2014-07-30 |
| US20140030237A1 (en) | 2014-01-30 |
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