TW201300409A - 用於治療癌症及慢性感染之具有促效劑活性之介白素-2(il-2)衍生物多肽 - Google Patents
用於治療癌症及慢性感染之具有促效劑活性之介白素-2(il-2)衍生物多肽 Download PDFInfo
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Abstract
本發明關於與人IL-2共有一級序列(除了已發生變異之數個胺基酸外)之多肽。該被引入之突變實質上降低這些多肽在活體外和活體內刺激調節性T細胞(T CD4+CD25+FoxP3+)之能力,而使其在小鼠之可移植腫瘤的療法中更有效。此外,本發明亦包括這些突變之變種於單獨使用或與用於疾病(諸如與調節性T細胞(Tregs)之活性有關之癌症或感染)療法之疫苗組合時的治療用途。本發明之另一面向係關於包含所揭露之多肽作為活性成分之醫藥組成物。最後,本發明關於所揭露之多肽及醫藥組成物由於其對疾病(諸如癌症及慢性感染疾病)之免疫系統的調節作用而具有之治療用途。
Description
本發明關於免疫學。其特別關於藉由具有原始分子之促效劑作用(但卻出人意料地顯示出優越療效)的天然分子類似物來治療性調節免疫系統。
介白素2(IL-2)為最早被提出之T細胞生長因子。自從被發現後,IL-2被觀察到具有在活體外促進T細胞增殖及存活的能力(Smith,KA.(1988) Science. 240,1169-76)並在T病毒感染(Blattman,JN,et al.(2003) Nat Med 9,540-7)或疫苗(Fishman,M.,et al.(2008) J Immunother. 31,72-80,Kudo-Saito,C.,et al.(2007) Cancer Immunol Immunother. 56,1897-910;Lin,CT.,et al.(2007) Immunol Lett. 114,86-93)的情況中加強免疫反應。然而,此IL-2作為T免疫反應之促進劑的傳統角色最近已由眾多顯示出此細胞因子為用於天然調節性T細胞CD4+CD25+FoxP3+(Tregs)的穩態生長因子(homeostatic growth factor)之實驗數據而受到質疑(Almeida,AR.,et al.(2002) J Immunol. 169,4850-60;de la Rosa,M.,et al.(2004) Eur J Immunol. 34,2480-8,Malek;TR,et al.(2004) Nat Rev Immunol. 4,665-74)。介白素-2亦已被提出在調節性T細胞抑制其他效應子細胞(諸如CD4 T輔助細胞、細胞毒性CD8 T細胞及天然殺手(NK)細胞)之活性及擴充的機制中擔任主要角色。特別是,最近已提出調節性T細胞抑制其他T細胞,誘導IL-2之(levels)局部降低(Pandiyan,P.,et al.(2007) Nat Immunol. 8,1353-1362)。此抑製效果係基於:a)其直接抑制該效應子T細胞產生新IL-2的能力(Almeida,AR.,et al.(2002) J Immunol. 169,4850-60;Takahashi,T.,et al.(1998) Int Immunol. 10,1969-80;Thornton,AM.,et al.(1998) J Exp Med 188,287-96;Wolf,M.,et al.(2001) Eur J Immunol. 31,1637-45);b)其隔離、內化及迅速降解存在於其微環境中之IL-2的能力(Pandiyan,P.,et al.(2007) Nat Immunol. 8,1353-62)及c)其過度表現IL-2受體之α鏈的能力(Kuniyasu,Y.,et al.(2000) Int Immunol. 12,1145-1155),此能力使IL-2在濃度低時可更有效地利用。
總之,IL-2為一種與不同細胞群之生物活性非常有關之高度多效性細胞因子。此性質使IL-2為調節免疫反應之重要節點,使其成為具有吸引力之療法及複雜之免疫調節的目標。
IL-2已用於癌症療法中數年。尤其是,有數個國家核准使用高劑量來治療轉移性黑色素瘤及腎細胞癌。然而,將IL-2直接用於患者中係嚴重受限於其毒性效果及低療效。正因如此,僅20%之符合條件的患者接受以IL-2為基礎之療法且那些接受此治療之患者中僅17%顯示出目標反應。在臨床設定中,此種嚴重失敗的可能解釋為使用天然IL-2進行之療法亦刺激調節性T細胞群(Ahmadzadeh,M.,et al.(2006) Blood. 107,2409-14),這抑制了所需之免疫刺激。現今有大量之臨床前證據支持此理念。特別是,在小鼠模型中之實驗顯示出注入活體內之IL-2的主要活性為穩態擴充天然調節性T細胞。現已開發數種策略來減輕IL-2療法的毒性作用。這些策略中有些係以使用IL-2之突變的變種為基礎,該IL-2之突變的變種係經設計以增加此分子主要藉由高親和力受體(α、β及γ鏈),而非藉由中度親和力受體(β及γ鏈)傳信的能力。其基本理念為促進T細胞中之傳信,而非NK細胞中之傳信(咸信此傳信係造成所觀察到之毒性作用的原因)。下列發明為這方面之成果:美國專利案7,186,804,美國專利案7,105,653、美國專利案6,955,807、美國專利案5,229,109、美國專利申請案20050142106。重要的是要注意這些發明中無一關於IL-2之突變蛋白(mutein),該IL-2之突變蛋白基於其刺激天然調節性T細胞的能力降低,因而在活體內之療效高於天然IL-2。
現已創造出意圖藉由,例如改良其蛋白折疊或增加其在血液中之壽命來增加其藥學活性的其他IL-2突變變種。其中,下列發明為這方面之成果:美國專利案第4,959,314號、美國專利案第5,116,943號、美國專利案第4,853,332號。同樣地,這些突變蛋白中無一具有降低之活化調節性T細胞的能力或顯示出較佳之療效。
最後,應提及的是,文獻中提出許多可在活體內調節或降低調節性T細胞之活性的治療劑(Kreitman,R.J.(2009) Curr Pharm Des. 15,2652-64;Litzinger,M.T.,Fernando,R.,Curiel,T.J.,Grosenbach,D.W.,Schlom,J. and Palena,C.(2007) Blood. 110,3192-201;Morse,M.A.,Hobeika,A.C.,Osada,T.,Serra,D.,Niedzwiecki,D.,Lyerly,H.K. and Clay,T.M.(2008) Blood. 112,610-8;Onizuka,S.,Tawara,I.,Shimizu,J.,Sakaguchi,S.,Fujita,T. and Nakayama,E.(1999) Cancer Res. 59,3128-33;Quezada,S.A.,Peggs,K.S.,Curran,M.A. and Allison,J.P.(2006) J Clin Invest. 116,1935-45)。這些治療劑已在動物模型中或甚至在患者中進行測試,作為癌症之直接療法或加強疫苗之效果。亦有一些報告提出調節IL-2之活性,尤其是單株抗體之活性(Boyman,O.,Kovar,M.,Rubinstein,M.P.,Surh,C.D. and Sprent,J.(2006) Science. 311,1924-1927;Boyman,O.,et al.(2006) Expert Opin Biol Ther. 6,1323-31;Kamimura,D.,et al.(2006) J Immunol. 177,306-14;Murakami,M.,Sakamoto,A.,Bender,J.,Kappler,J. and Marrack,P.(2002) Proc Natl Acad Sci USA. 99,8832-7;Tomala,J.,Chmelova,H.,Mrkvan,T.,Rihova,B. and Kovar,M.(2009) J Immunol. 183,4904-4912),以促進更好或更有效之免疫反應。然而,據我們所知,文獻中未報導以IL-2之突變的變種為基礎時顯示出基於其刺激天然調節性T細胞的能力降低可能取得更佳之療效。
本發明關於產製在可移植之小鼠腫瘤模型中顯示出具有優於天然IL-2之療效的IL-2之突變變種。這些突變蛋白之特徵為其可作為IL-2活性之部分促效劑且由於其在活體外及/或活體內刺激天然調節性T細胞(TCD4+CD25+FoxP3+)之能力特別低而被選定。這些突變蛋白之活體內療效提供改善惡性腫瘤之IL-2療法的實用解決方案。尤其是,這些突變蛋白將提供克服天然IL-2療法中所觀察到之侷限性(這些侷限性係來自於其經證明之在活體內擴充天然調節性T細胞之能力)的方法。本發明關於與人IL-2共有其一級序列(除了已發生突變之數個胺基酸外)之多肽。發生的突變實質上降低這些多肽在活體外及活體內刺激調節性T細胞(TCD4+CD25+FoxP3+)之能力,而產生在小鼠之可移植腫瘤的療法中更有效之IL-2a。本發明亦包括這些突變之變種於單獨使用或與用於疾病(諸如與調節性T細胞(Treg)之活性有關之癌症或感染)療法之疫苗組合時的治療用途。
本發明可大幅改善目前以IL-2為基礎之免疫調節策略,無論是用於癌症之直接療法或與不同之疫苗組合。尤其是,以本文所述之突變的變種來取代天然IL-2將防止調節性T細胞擴充(此調節性T細胞擴充將顯著降低所需之治療效果)。
本發明關於其表觀分子量至少為15 kD之100至500個胺基酸長(較佳之大小為具有140個胺基酸殘基)之多肽。這些多肽與天然IL-2保持超過90%之高度序列一致性。在這些多肽序列之一區中,與天然IL-2相比較,其包括3至6個突變。在這些位置中,這些多肽引入與天然IL-2之相同位置中不同之胺基酸殘基而發生突變。該取代原始殘基之胺基酸係經過選擇以使其具有與原始胺基酸相當不同之理化性質,極性殘基改為非極性殘基,不帶電殘基改為帶電殘基,大殘基改為小殘基,酸性改為鹼性等變化。
本發明之多肽可稱為免疫調節多肽、IL-2類似物或IL-2突變蛋白,等名稱。這些多肽係根據IL-2受體複合物之三維結構(可在PDB之公共數據庫取得)設計,IL-2中引入突變之位置主要係對應於明顯暴露於溶劑(exposed to the solvent)且高度保留於來自不同物種之IL-2(自Swissprot數據庫取得之序列)中之胺基酸。前文提及之暴露於溶劑的胺基酸類型係使用用於視化蛋白質結構之生物資訊軟體(諸如RASMOL、SwissPDBviewer等)來鑑定。IL-2序列中之保留位置係使用用於多序列比對之生物資訊軟體鑑定,如:Fasta、ClusterW等。
本發明之多肽可藉由各種策略(包括合成蛋白質)取得。其亦可藉由基因工程技術取得,例如:將其表現在細菌(諸如E. coli之大腸桿菌或其他細菌)及哺乳動物細胞(諸如NSO細胞或其他哺乳動物細胞)中。在特定位置處之點突變亦可藉由定點致突變技術,以聚合酶鏈反應分析(PCR)取得。
令人意外地,本發明者發現這些突變蛋白關於天然IL-2之傳統用途的實質利益。此利益在於彼等於腫瘤療法中來自於其防止調節性T細胞擴充之能力而增加之有效性。
本發明之多肽係根據以下性質選擇:
1)天然IL-2之促效劑作用。此性質可以直接在活體外增殖分析中,藉由依賴IL-2之細胞株(諸如CTLL2或Kitt225)直接評估,或以使用小鼠和/或人類T淋巴細胞之混合物的分析來評估。在這些試驗中,這些突變蛋白必須具有較天然IL-2低5至50倍之特異性刺激活性。
2)與天然IL-2相較下,喪失在活體外和/或在活體內刺激調節性T細胞群的能力。此性質可,例如,經由研究本發明之突變蛋白與那些天然IL-2相較下直接誘導TCD4+CD25+細胞(自無免疫力小鼠純化並在活體外以抗CD3抗體刺激)擴充之能力來評估。亦可經由腹腔內途徑或皮下途徑將這些突變蛋白或天然IL-2注射入小鼠中歷經5天並評估其對調節性T細胞(TCD4+CD25+FoxP3+)群之擴充或增殖速度增加的效果來估計。在這些試驗中,突變之IL-2對Treg細胞之活性必須較天然IL-2之活性至少低1000倍。
3)在動物模型中與天然IL-2相關之治療效果提高。此性質可,例如,在可移植之腫瘤模型(如:B16黑色素瘤)中比較使用突變蛋白與天然IL-2作為單一療法之抗癌或抗腫瘤轉移效果來進行評估。亦可透過對所欲疫苗之細胞和/或體液免疫反應的促成效果來評估此性質。在包含相等之總蛋白質質量的IL-2及突變蛋白劑量中,突變蛋白必須顯示出高於天然IL-2之療效。
本發明特別關於表1中所詳細指明之突變蛋白。這些突變蛋白具有數種可賦予彼等上述性質之胺基酸取代。
本發明亦包括上文提及之IL-2突變蛋白類別,尤其是表1中所描述者的額外修改。無論是增加彼等對IL-2受體之特殊組分的親和力,但不影響,甚至改善其不刺激調節性T細胞之促效劑特徵,或改善彼等在活體內之藥效學:增加半衰期或減少彼等被T細胞內化。這些額外之突變可能經由以生物資訊工具進行合理設計來取得,或使用具不同性質之組合分子庫(噬菌體庫、酵母菌或細菌中之基因表現庫)來取得。
本發明之另一面向係關於包含與載體蛋白耦合之任何上述免疫調節多肽的融合蛋白。該載體蛋白可為白蛋白或人免疫球蛋白之Fc區。
本發明亦包括含有藉由本發明之方式揭露之IL-2的突變蛋白及其類似物作為其活性成分的醫藥組成物以及該醫藥組成物於增強疾病(諸如與調節性T細胞特別相關之癌症或慢性感染)中之天然或由疫苗誘導之免疫反應的潛在治療應用。
在其治療應用方面,應將本發明之多肽單獨或與促進或增強本發明多肽之治療作用的其他多肽或其他物質一起投予患有該疾病之個體。投服途徑可為本技藝描述之任何用於腸胃道外投服藥物的投服途徑。較佳地,本發明之多肽應經由靜脈內、肌肉內、皮下或腫瘤內途徑投服。
此處所描述之多肽亦可作為天然IL-2之替代品,以用於治療癌症及慢性感染疾病或增強對疫苗之細胞及/或體液免疫反應之醫藥組成物的一部分之形式投服。本發明之多肽可與用於癌症之治療性疫苗或與用於其中牽涉到調節性T細胞之感染疾病的預防性疫苗一起使用。
為了取得所需之治療效果,本發明之多肽應以足夠高之劑量投服以確保其在與研究之疾病相關的周邊淋巴結或周圍部位中的濃度,且係在該突變蛋白顯示出免疫刺激作用的濃度範圍內。因此,所討論之劑量應根據研究之疾病類型及投服途徑調整。例如:在腫瘤療法的情況中,應調整劑量以取得在腫瘤內及/或局部區域淋巴結中之突變蛋白的濃度,從而確保刺激抗腫瘤免疫反應。欲探查之劑量範圍可以從每劑量數百微克至數百毫克。在以突變蛋白取代傳統療法中之天然IL-2的應用中,所使用之突變蛋白的劑量在活性上應低於或等於傳統上使用之天然IL-2的活性(使用以CTLL2株進行之分析測定)。
欲施用之投服次數亦應根據所討論之突變蛋白的生物分佈進行調整。一般而言,上述之有效水準應保持連續之2至30天。應注意的是,例如,若突變蛋白與載體蛋白耦合,其投服頻率應據此調整。對其中該天然IL-2被取代之應用而言,該突變蛋白之投服計劃可能類似於傳統療法中所使用者。
治療作用應由疾病症狀之全部或部分緩解來了解。在癌症中,腫瘤體積縮小或復發前之時間延長等將為該疾病之緩解標準。本發明之多肽在腫瘤(諸如黑色素瘤和腎腫瘤)療法中特別有用。
使用數據庫PDB(蛋白質數據庫)中報告之人IL-2的結構及可在Swissprot數據庫中取得之各種物種的IL-2胺基酸序列作為基礎,從生物信息學技術計算設計該突變蛋白。設計數種在溶劑暴露及高度保留之殘基中包含3至6種突變(引入非保留性胺基酸取代)的突變蛋白。從來自pET28a載體中之質體構造將這些突變蛋白(在胺基端包含一具有6個組胺酸之靶的序列)表現在大腸桿菌中。藉由逆相色層分析法純化該突變蛋白(第1圖)並得到高純度(>95%)。從所得之突變蛋白在活體外和活體內之實驗分析中的性質選出顯示出具有本發明主文中所述之3種基本性質的突變蛋白。從所有建構之突變蛋白中,表1描述一組特定突變,其具有所需之作為IL-2活性促效劑的性質,但不會明顯刺激調節性T細胞,且顯示出在治療可移植之小鼠腫瘤時具有較天然IL-2為佳之療效。表2顯示出其他未顯示出所需性質之建構的突變蛋白。
第2圖說明表1中提及之突變蛋白如何與CTLL2細胞株表面上之IL-2受體的組分結合(第2a圖)。該建構之突變蛋白係結合至已知其表面上具有IL-2之高親和性及中度親和性受體的CTLL2細胞。在吾人之分析中所偵測之結合作用顯示出類似於以天然IL-2取得者。第2b圖說明顯示於表1中之突變蛋白刺激CTLL2細胞株生長的能力(第2b圖)。在此分析中,這些突變蛋白係作為IL-2活性之部分促效劑。其特異活性低於天然IL-2之5至50倍。
表1中描述之突變蛋白在活體外顯示出非常低之刺激調節性T細胞的能力(第3圖)。如此圖中所示,雖然天然IL-2能夠誘導被與盤結合(plate-bound)之抗CD3抗體刺激的調節性T細胞(T CD4+CD25+FoxP3+)強效增殖。表1中描述之突變蛋白的質量濃度明顯高於天然IL-2之質量濃度時並不會刺激調節性T細胞。必須指出,在使用CTLL2株之增殖分析中即使增加欲使用之突變蛋白的量,從而使用在活性上與天然IL-2相等之量時上述結果仍有效。表1中所描述之突變蛋白通常顯現出刺激調節性T細胞的能力較天然IL-2低至少1000倍以上。
表1中描述之突變蛋白顯示出活體內免疫刺激能力增加。第4a、b圖顯示出以經由腹膜內途徑投服之二個20微克突變蛋白日劑量治療歷經5天後,該突變蛋白如何在無免疫力小鼠中誘導較天然IL-2所誘導者為大之脾腫大。此刺激與效應子群(如T CD8+淋巴細胞)明顯增加相關。在相關之觀察方面,我們可以陳述,相對於以天然IL-2治療時所觀察到者,以這些突變蛋白治療不會刺激調節性T細胞(T CD4+CD25+FoxP3+)擴充(第4c、d圖)。
在小鼠可移植之腫瘤模型中證明設計之突變蛋白的療效增加。表1中所描述之突變蛋白顯示出在MB16小鼠黑色素瘤模型中治療肺部腫瘤轉移的效力增加。第5圖顯示出以經由腹膜內途徑投服之二個20微克突變蛋白日劑量治療歷經5天後,該突變蛋白如何具有強效之抗腫瘤轉移作用,此情況在以相等劑量之天然IL-2治療的組別中未觀察到。
證明設計之突變蛋白促成抗腫瘤疫苗作用之能力。使用具有EG7細胞株(此為經基因工程修改之用於表現OVA抗原的腫瘤細胞株)之原發性腫瘤模型。以OVA抗原(經佐以單獨之VSSP佐劑或加上突變蛋白)接種帶有腫瘤之小鼠。第6圖顯示出以組合物治療之小鼠腫瘤生長減少的程度大於僅以疫苗治療之小鼠。
<110> 分子免疫學中心
<120> 用於治療癌症及慢性感染之具有促效劑活性之介白素-2(IL-2)衍生物多肽
<130> 402010CU00
<140> CU/P/2010/216
<141> 2010-11-12
<160> 6
<170> PatentIn version 3.5
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第1圖取得突變蛋白。a)藉由在SDS-聚丙烯醯胺凝膠(SDS-PAGE)中電泳評估突變蛋白在大腸桿菌株BL21 DE3中之表現水準,第1道:BL21 DE3株之總蛋白質,表現之陰性對照組;第2及3道:在此株中達到之表現水準的兩個實例,箭頭表示對應於突變蛋白之長帶(band)。b)顯示該蛋白質之主要最終純化步驟的逆相色層分析圖,箭頭表示對應於所欲蛋白之波峰。c)藉由SDS-PAGE評估突變蛋白的純化,1:包涵體分離過程之結果,2:藉由逆相色層分析純化後取得之突變蛋白。
第2圖IL-2突變蛋白之促效劑性質的評估。a)藉由流式細胞技術測量突變蛋白與CTLL2細胞株之表面結合的能力。使用抗6His標識單株抗體偵測IL-2及突變蛋白二者。b)圖表顯示出與天然IL-2相比較,該突變蛋白誘導IL-2依賴性T細胞株CTLL2增殖之能力。藉由納入MTT來測定增殖作用。
第3圖突變蛋白不會在活體外誘導調節性T細胞增殖。a)流式細胞技術圖顯示出從C57BL/6小鼠淋巴結純化之CD3+CD4+CD25+群的純度。b)在活體外以抗CD3單株抗體刺激Treg細胞,並投予彼等濃度為0.5毫微克/毫升之天然IL-2或濃度為32毫微克/毫升之突變蛋白持續72小時,該圖形顯示出與未添加細胞因子之對照組相比較,每次治療後回復之活細胞數。所選定之濃度相當於各分子誘導CTLL2株產生相同增殖之濃度。
第4圖評估以突變蛋白治療時對細胞群增殖之影響。a)定量以突變蛋白治療5天之小鼠的脾臟之相對重量。經治療之小鼠的脾臟重量統計上高於對照組之脾臟重量。克魯斯卡爾沃利斯(Kruskal-Wallis)非參數測試及Dunn多重比較。b)測量T CD8+細胞群,該圖形顯示出此細胞群之百分比。
第5圖在黑色素瘤MB16F0株之實驗性腫瘤轉移模型中該突變蛋白在減少腫瘤轉移上較天然IL-2更有效。a)每次治療之代表性肺部照片。b)定量各組中之肺部腫瘤轉移。
第6圖以突變蛋白及OVA/VSSP疫苗之組合物治療時使疫苗之抗腫瘤作用成為可能。以單獨之OVA/VSSP疫苗或將其與突變蛋白組合來治療帶有腫瘤之小鼠。圖形顯示出腫瘤之生長曲線,以組合物治療之組別表現出腫瘤生長減少較多,統計上不同於該對照組。
Claims (28)
- 一種介白素-2(IL-2)之促效劑多肽,其特徵為與天然IL-2序列具95%之同源性且其中該多肽在活體外及/或活體內刺激調節性T細胞時效力至少低1000倍且在活體內顯示出較高之療效。
- 如申請專利範圍第1項之多肽,其包含突變R38K、F42I、Y45N、E62L、E68V。
- 如申請專利範圍第1項之多肽,其包含突變R38K、F42Q、Y45E、E68V。
- 如申請專利範圍第1項之多肽,其包含突變R38A、F42I、Y45N、E62L、E68V。
- 如申請專利範圍第1項之多肽,其包含突變R38K、F42k、Y45R、E62L、E68V。
- 如申請專利範圍第1項之多肽,其包含突變R38K、F42Q、Y45E、E68V。
- 如申請專利範圍第1項之多肽,其包含突變R38A、F42A、Y45A、E62A。
- 一種融合蛋白,其包含與載體蛋白耦合之如申請專利範圍第1至7項中任一項之免疫調節多肽。
- 如申請專利範圍第8項之融合蛋白,其中該載體蛋白為白蛋白。
- 如申請專利範圍第8項之融合蛋白,其中該載體蛋白為人免疫球蛋白之Fc區。
- 一種有用於治療癌症及慢性感染疾病之醫藥組成物,其特徵為包含如申請專利範圍第1至7項中任一項之多肽作為活性成分。
- 如申請專利範圍第11項之醫藥組成物,其包含一或多種如申請專利範圍第1至7項中所描述之多肽作為活性成分。
- 一種有用於治療癌症及慢性感染疾病之醫藥組成物,其包含如申請專利範圍第8至10項中任一項所描述之融合蛋白作為活性成分。
- 一種如申請專利範圍第1至7項中任一項之多肽於取代天然IL-2來直接治療惡性腫瘤的用途。
- 一種如申請專利範圍第1至7項中任一項之多肽於取代天然IL-2來增強對疫苗之細胞及/或體液免疫反應的用途。
- 如申請專利範圍第15項之用途,用疫苗促進時,該疫苗為用於癌症之治療性疫苗。
- 如申請專利範圍第15項之用途,用疫苗增強時,該疫苗為用於與調節性T細胞有關之感染疾病的疫苗。
- 如申請專利範圍第1至7項中任一項之多肽,其係用於製造有用於治療慢性疾病之藥劑。
- 如申請專利範圍第1至7項中任一項之多肽,其係用於製造有用於癌症療法中之藥劑。
- 如申請專利範圍第1至7項中任一項之多肽,其係用於製造有用於慢性感染疾病療法中之藥劑。
- 一種如申請專利範圍第1至11項中任一項之多肽於慢性疾病療法中之用途。
- 一種如申請專利範圍第1至11項中任一項之多肽於癌症療法中之用途。
- 一種如申請專利範圍第1至11項中任一項之多肽於慢性感染疾病療法中之用途。
- 一種如申請專利範圍第8至10項中任一項之融合蛋白於慢性疾病療法中之用途。
- 一種如申請專利範圍第8至10項中任一項之融合蛋白於癌症療法中之用途。
- 一種如申請專利範圍第8至10項中任一項之融合蛋白於慢性疾病療法中之用途。
- 如申請專利範圍第1至7項中任一項之多肽,其係用於製造調節免疫系統之藥物。
- 一種如申請專利範圍第1至7項中任一項之多肽及彼等於引入新突變來增加其對IL-2之不同組分的結合親和力時之應用。
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