TWI793099B - 用於胜肽遞送的穩定乳液及其製造方法 - Google Patents
用於胜肽遞送的穩定乳液及其製造方法 Download PDFInfo
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Abstract
本發明關於一種用於製造工業規模的即用型胜肽乳液之方法,其包含於低剪切條件下將至少二胜肽的懸浮液與至少一佐劑進行乳化的步驟。本發明亦關於根據此方法可獲得的即用型乳液。本發明允許遞送可放大的胜肽乳液,其保持其完整性並滿足藥物無菌產品所需的要求。
Description
本發明關於一種工業規模的即用型胜肽乳液的製造方法及根據此方法可得到的即用型乳液。本發明允許遞送胜肽的可調式乳液(scalable emulsion),其保持其完整性並實現藥物無菌產品所需的要求。
依循治療癌症的新方法係關於發展包含胜肽組合之改善的癌症疫苗。
然而,胜肽聚集的風險和可能導致免疫原性降低的不溶性胜肽的存在是發展蛋白藥物或胜肽藥物的反復障礙。當在同一製劑中混合時,此聚集作用或脫醯胺作用(deamidation)的風險在胜肽類之間增加。
在臨床前或臨床試驗期間,所有胜肽藥物候選的約95%通常由於與低溶解度或聚集問題有關的問題而被廢棄。由於聚集作用可能不僅危及其生體可用率和治療效果,也增加不良反應的風險,因而聚集作用亦是發展蛋白質類的藥物的最重大的障礙之一(Interpretation of the dissolution of insoluble peptide sequences based on the acid-base properties of the solvent L Malavolta et al 2006, Protein Sci. 2006 Jun; 15(6): 1476–1488)。
除非整個序列由疏水性胺基酸(例如,A、F、I、L、M、P、V、W、Y、α-胺基丁酸(alpha-amino butyric acid)、b-胺基丙胺酸(b-amino alanine)、正白胺酸(norleucine))組成,否則短於5個殘基的胜肽通常可溶於水或水性緩衝液中。含有50%及更多疏水性殘基的胜肽可能為不溶性或僅部分溶於水性溶液中。含有高比例的D、E、H、K、N、Q、R、S、T、Y的胜肽能夠建立分子間氫鍵(即,交聯),因此在水性溶液中形成凝膠。
胜肽的聚集體分類為水溶性或不溶性以及共價(包括共價鍵的形成,通常為二硫鍵結)或氫鍵(弱交互作用)。治療性蛋白質經由共價鍵的自締合(Self-association)通常是不可逆的,而經由弱交互作用形成的聚集體可因蛋白質濃度、溫度和pH的變化而為可逆的。因此,聚集體的尺寸範圍可從微小的、不可見的,非可過濾粒子到肉眼可見的大沉澱物。另外,部分聚集體可為靜態,而其他可為動態。
一些製造階段影響化學降解的風險,其增加物理降解和聚集體形成的風險。例如,較高濃度的蛋白質或胜肽製劑,以及因溶液pH、溫度、緩衝液選擇的變化可能增加聚集的可能性。此外,在疫苗生產中進行的乳化步驟亦可能導致胜肽降解及聚集作用。允許形成油中水(W/O)乳液之含有佐劑的疫苗製劑通過在注射部位形成積存(depot)來誘導免疫反應,並且確實可行性高。然而,當胜肽的組合包含可溶性肽及不溶性肽時,均質化和乳化製程是個問題。由於乳化是局部遞送胜肽和免疫呈遞(immune presentation)的關鍵因素,因此乳液中的此胜肽的穩定性對於安全性和免疫原性至關重要。於可溶狀態或不可溶狀態的胜肽對於溫度及攪拌皆敏感,其對於氧化敏感,不可溶胜肽及可溶胜肽的混合物可能在儲存期間呈現交叉反應性問題(cross-reactivity concerns),且用於混合此組合的機械力可能改變胜肽。
有鑑於這些缺點,包含胜肽組合的疫苗製劑相當於臨時製備的。
例如,最近研究以組合胜肽URLC19-177、CDCA1-56、TTK-567、VEGFR1-770及VEGFR2-169進行;所有五種胜肽預期結合至HLA-A24分子。結合胜肽皆以20 mg/ml濃度溶解於DMSO中,並儲存於−80°C。將其與佐劑(不完全佛蘭氏佐劑IFA或Montanide®
ISA 51)混合之後於床位(bed place)注射(Suzuki H. et al 2013 “Multiple therapeutic peptide vaccines consisting of combined novel cancer testis antigens and anti-angiogenic peptides for patients with non-small cell lung cancer.” Journal of Translational Medicine 2013)。相似的結合胜肽以相同過程使用(結合至HLA-A*24分子的TTK-567、URLC10-177、KOC1-508、VEGFR1-1084、VEGFR2-169)(Iinuma H. et al “Phase I clinical study of multiple epitope peptide vaccine combined with chemoradiation therapy in esophageal cancer patients”- Journal of Translational Medicine 2014)。5個自RNF43、TOMM34、KOC1、VEGFR1及VEGFR2衍生的HLA-A*2402限制的胜肽亦使用於組合中[RNF43-721、TOMM34-299、KOC1(IMP-3)-508、VEGFR1-1084及VEGFR2-169] (Hazama S. et al “A phase I study of combination vaccine treatment of five therapeutic epitope-peptides for metastatic colorectal cancer; safety, immunological response, and clinical outcome” Journal of Translational Medicine 2014)。
在注射至患者之前,首先將上述最近文獻中提到的所有胜肽組合溶液化,接著與佐劑混合。該過程避免製備其中需要佐劑中的胜肽的長期穩定性的乳液。
相反地,於WO 2004/094454中揭露包含胜肽混合物的即用型疫苗的實例。在此文件中,胜肽的組合以反相乳液(reverse emulsion)的形式皮下施予。為了製備該乳液,將各種可溶性和不溶性胜肽在不同的介質中進行溶液化,以提供三種單獨的溶液,然後將其冷卻,進行無菌過濾並混合在一起,以獲得懸浮液,接著將其pH調整至7。此懸浮液與包含自甘露醇及合成或植物來源的純化油酸所獲得的甘露醇單油酸酯(mannide mono-oleate)的油中水(W/O)乳化劑混合。該乳化劑可獲得含有分散有胜肽的細水滴的油中水乳液。此乳液結構反而提供強力且持久的免疫力。
胜肽的乳化需要強力的混合器。均質化使用機械力來混合自佐劑的油及自胜肽溶液的水滴。高剪切力及機械力對於產生精細分散的液滴為重要的。此乳液通常考慮到胜肽化學物質在混合製程中賦予阻力而證實為困難的。藉由高壓均質器實現的高剪切可克服該阻力。因此,佐劑供應商推薦具有高剪切的胜肽的乳化。例如,描述在2007年4月以Montanide®
ISA 50 V2出售的佐劑的指南中,SEPPIC建議使用如Silverson®
L4RT的高剪切混合器以4000rpm將此佐劑與水性抗原性介質混合,以獲得穩定且有效的疫苗。
如上所述,於WO 2004/094454中,胜肽懸浮液與佐劑的混合是利用Silverson®
L4RT均質器以8,000 rpm旋轉30分鐘來執行。該設備包含具有轉子的混合工作台(workhead),該轉子提供有圍繞軸線放射狀佈置的葉片,並且將由轉子吸取的流體放射狀地引導至與轉子同心並與轉子短距離設置的定子。定子包含提供在網格中的孔。由於其在轉子葉片的端部與定子的內壁之間研磨並且朝向混合工作台的側面以高速擠出穿過定子中的穿孔,因此此轉子-定子系統提供於WO 2004/094454中形成的具有高剪切力的乳液。
然而,本發明發現此製程的放大無法產生提供長期穩定性的胜肽之乳液。具體而言,當放大上述製程時,申請人注意到,藉由反相HPLC所含的胜肽的劑量依據所測試的批次而導致不同的值。其在WO 2004/094454中注意到的是,其中聲稱觀察到胜肽濃度的誤差高達30%。由於預期濃度的50%的規格被認為是釋放及穩定性規範,因此此變異性對於最終藥物產品為可接受的。雖然此變異性在早期臨床研究中保持在可接受的範圍內,但對於進階臨床試驗的目的,盡可能降低其是必要的,以便符合部分藥物立法的嚴格要求,更重要的是確保遞送處於穩定乳化狀態的胜肽並保證各胜肽的免疫原性。本發明人已進行廣泛的研究,以克服此問題。在此情況下,本發明者已顯示,特別是當組合由可溶性胜肽及不溶性胜肽製成時,獲得在癌症疫苗中的胜肽與佐劑的可用乳化所需的攪拌速度及持續時間可能改變胜肽的完整性並降低其效力。
發現高剪切力和高速的乳化方法當在大規模使用時導致胜肽降解及/或聚集。此外,習知技術中使用的高剪切混合器產生熱,因此需要恆定冷卻混合器,以避免熱敏感胜肽可能的降解。當放大此製程時,為了依據氧化胺基酸相對於功能性或類表位域(epitope-like domains)胜肽的位置而避免可能不利於影響其效力的胜肽氧化,此冷卻步驟的準確控制似乎是一個挑戰。氧化亦可能改變胜肽的物理化學特性並導致聚集作用。此現象反而可能損害含有此胜肽的藥物的治療效果所需的安全性和遞送,並且亦增加了免疫原性反應的風險。
因此,本發明尋求用於克服上述問題的手段,並因而提供在工業規模上容易執行的製程,以製備已保留胜肽的化學完整性的可注射胜肽乳液,具體而言為防止或減少胜肽降解(例如,氧化及/或脫醯胺作用)及聚集,而不會負面影響乳液的物理穩定性,以使各胜肽在穩定條件下遞送。此外,需要可重複製程。
本申請意外地發現,上述需求可以藉由其中在比目前使用的乳化條件更溫和的條件下製備胜肽乳液的製程來滿足。具體而言,與習知技術建議的相反,其避免高速及高剪切力,並且更意外的是,即使在低速下也不需長持續時間的混合。因此,保護不同溶解度的胜肽免於氧化壓力,而不需要在混合時冷卻乳液,並且防止其聚集。因而與習知技術如WO 2004/094454相比,肽胜濃度的變異性顯著降低。因此,本發明可獲得用於最佳遞送胜肽的穩定乳液,其由於胜肽免疫遞呈所需的積存作用而對於穩定免疫原性為所需的。由於先前即時製備的製程為依賴操作者,因而此製程相較於先前用於即時製備的製程更進一步為可再現的。其可製造大量的乳液,因而可適用於工業規模。
因此本發明提供一種於工業規模上製造即用型胜肽乳液的方法,其包含於100至1000 rpm之間的轉速,在2~15分鐘期間的低剪切條件下將至少二胜肽的懸浮液與至少一佐劑進行乳化的步驟。
較佳地,該胜肽包含至少一可溶性胜肽及至少一非可溶性胜肽。具體而言,該胜肽係選自由胜肽KVFGSLAFV(SEQ ID NO:7)、胜肽YLSGADLNL(SEQ ID NO:8)、具有B指示為α-胺異丁酸(alpha-aminobutyric acid)的胜肽KLBPVQLWV(SEQ ID NO:6)、胜肽SMPPPGTRV(SEQ ID NO:5)、胜肽IMIGHLVGV(SEQ ID NO:9)、胜肽LLTFWNPPV(SEQ ID NO:4)、胜肽RLLQETELV(SEQ ID NO:2)、具有X及a
分別指示為環己基丙胺酸(cyclohexylalanine)及d-丙胺酸(d-alanine)的胜肽a
KXVAAWTLKAAa
(SEQ ID NO:1)、胜肽YLQLVFGIEV(SEQ ID NO:3)及胜肽KVAEIVHFL(SEQ ID NO:10)所組成的群組。在特定實施例中,懸浮液包含胜肽KVFGSLAFV(SEQ ID NO:7)、胜肽YLSGADLNL(SEQ ID NO:8)、胜肽KLBPVQLWV(SEQ ID NO:6)、胜肽SMPPPGTRV(SEQ ID NO:5)、胜肽IMIGHLVGV(SEQ ID NO:9)、胜肽LLTFWNPPV(SEQ ID NO:4)、胜肽RLLQETELV(SEQ ID NO:2)、具有X及a
分別指示為環己基丙胺酸及d-丙胺酸的胜肽a
KXVAAWTLKAAa
(SEQ ID NO:1)、胜肽YLQLVFGIEV(SEQ ID NO:3)及胜肽KVAEIVHFL(SEQ ID NO:10)的組合。
較佳地,該佐劑由烴類油與油中水乳化劑的混合物所組成。具體而言,烴類油選自石蠟油、植物油、鯊烯、鯊烷或礦物油,且油中水乳化劑選自甘露醇單油酸酯及山梨糖醇酐單油酸酯(sorbitan mono-oleate)。在特定實施例中,烴類油為礦物油且油中水乳化劑選自甘露醇單油酸酯。
較佳地,佐劑與胜肽懸浮液的重量比範圍為10:1至1:10,較佳地為5:1至1:5的範圍且更佳為2:1至1:2的範圍,且又更佳為1:1。
較佳地,所有或部分的混合步驟是在惰性氣氛下,較佳地在氮氣下執行。
較佳地,乳液的體積大於5L,較佳地大於或等於10L。
在特定實施例中,胜肽懸浮液由下列方法所製備,該方法包含: a)製備至少三種不同的溶液A、溶液B及溶液C,其中: · 溶液A為酸性水性介質且包含具有X及a
分別指示為環己基丙胺酸及d-丙胺酸 (SEQ ID NO:1)的胜肽a
KXVAAWTLKAAa
(SEQ ID NO:1), · 溶液B為在任何胜肽加入之前為pH12.5至12.9之間的鹼性水性介質且溶液B包含胜肽YLSGADLNL(SEQ ID NO:8), · 溶液C為DMSO包含胜肽KVFGSLAFV(SEQ ID NO:7),且 · 溶液A及/或溶液B進一步包含選自的具有B指示為α-胺異丁酸的KLBPVQLWV(SEQ ID NO:6)、SMPPPGTRV(SEQ ID NO:5)、IMIGHLVGV(SEQ ID NO:9)、LLTFWNPPV(SEQ ID NO:4)、KVAEIVHFL(SEQ ID NO:10)、RLLQETELV(SEQ ID NO:2)及YLQLVFGIEV (SEQ ID NO:3)中的至少3種其他胜肽; b)混合該溶液,以形成懸浮液;以及 c)將懸浮液的pH調整至約7。
在一態樣中,溶液A包含a
KXVAAWTLKAAa
(SEQ ID NO:1)、SMPPPGTRV(SEQ ID NO:5)、IMIGHLVGV(SEQ ID NO:9)及KVAEIVHFL(SEQ ID NO:10),且溶液B包含YLSGADLNL(SEQ ID NO:8)、KLBPVQLWV(SEQ ID NO:6)、LLTFWNPPV(SEQ ID NO:4)、RLLQETELV(SEQ ID NO:2)及YLQLVFGIEV(SEQ ID NO:3)。
本發明亦關於一種可根據本發明之方法獲得或可獲得的即用型乳液,特別是用於治療癌症,較佳為HLA-2陽性癌症。具體而言,乳液中各胜肽的量的範圍為0.1至10 mg/ml,較佳為0.5至1 mg/ml,並且與用於製備乳液的量相差不超過10%。在一實施例中,乳液的D50為10 ± 1 µm。
本發明關於一種於工業規模自包含至少兩種胜肽的胜肽懸浮液製造即用型乳液的方法。這些胜肽通常不具相同溶解度且其較佳為使用至少一可溶性胜肽及至少一非可溶性胜肽的組合。
用語「非可溶性胜肽(non-soluble peptide)」係指在pH7.0 ± 1.0下溶解於水中的量小於60% w/v的胜肽,而「可溶性胜肽(soluble peptide)」係指在pH7.0 ± 1.0下溶解於水中的量至少60% w/v的胜肽。溶解度可藉由使濃度為1mg/ml的胜肽的水性溶液通過0.45μm過濾器並測量過濾器上剩餘的胜肽的量來評估。
藉由「工業規模(industrial scale)」,其表示製備體積大於5L,較佳為大於或等於10L的乳液。在一實施例中,體積可為50L、100L、200L、500L或1000L。
胜肽
根據本發明的較佳實施例,胜肽可選自腫瘤相關抗原(Tumor-associated antigen,TAA)表位及/或其類似物,較佳為HLA-A2結合TAA表位(HLA-A2 binding TAA epitopes)。
TAA表位可自一或多個標的,具體而言選自由CEA(癌胚抗原((Carcinoembryonic antigen)、p53、HER-2/neu、具體而言為MAGE-2及MAGE-3的MAGE(黑色素瘤抗原(Melanoma antigen))、LY6K(淋巴球抗原6複合物(Lymphocyte Antigen 6 Complex),Locus K)、CDCA1(細胞分裂週期相關1)(例如參照EP2186889)、IMP3(類胰島素生長因子II mRNA結合蛋白3(insulin-like growth factor-II mRNA-binding protein 3))(例如參照 WO11067920)、KIF20A(類致動蛋白(Kinesin-like protein))(例如參照 WO10047062)、FOXM1 (叉頭合蛋白M1(Forkhead box protein M1))(例如參照 EP2186889)、CDC45L(細胞分裂控制蛋白45同源物)、GPC3(glypican-3)(例如參照WO2015/173112)、CDH3(黏附蛋白3(Cadherin 3))、SPARC(分泌的蛋白質酸性及富含半胱胺酸)、DEPDC1(含有DEP域1(DEP domain containing 1))、MPHOSPH1(M期磷蛋白質1(M-PHASE PHOSPHOPROTEIN 1))(例如參照WO2013024582)、ME-1(蘋果酸酵素1(Malic Enzyme 1))、ENDC3B、PRDX5(過氧化物還原酶5(Peroxiredoxin-5))、GAS7(成長停滯特異性蛋白7(Growth arrest-specific protein 7))、HA-1(miHAg)(次要組織相容性抗原(Minor histocompatibility antigen)HA-1)、GAPDH(甘油醛-3-磷酸去氫酶(Glyceraldehyde 3-phosphate dehydrogenase))、HSP70(70 kD熱休克蛋白)、ACTININ、HAUS3(HAUS類augmin複合次單元3(augmin-like complex subunit 3))、CSNK1A1(酪蛋白激酶I同功型α(Casein kinase I isoform alpha))、CLPP(ATP依賴性Clp蛋白酶蛋白分解次單元(ATP-dependent Clp protease proteolytic subunit))及CDK4(週期素依賴性激酶4(Cyclin-dependent kinase 4))所組成的群組所衍生。在較佳實施例中,胜肽係為選擇及標的CEA、p53、HER-2/neu、MAGE-2及MAGE-3。
例如,胜肽包含選自由自WO 2004/094454、WO2014141683、WO2015173112、WO2015160928、WO2015/155537、WO2014162962、WO2014141652、WO2014136453、WO2014136453、WO2014127276、WO2014047085、WO2014041784、WO2013024582、WO2012073459、WO2013061594、WO2012169200、WO2011111392、WO2012053200、WO2012053206、WO2010137295、WO08047473、WO08102557、WO09109855、EP2186889、EP2186889、WO2010047062、WO2011067920及其類似文獻(其揭露內容於此併入作為參照)所揭露的胜肽。
根據本發明的具體實施例,胜肽係選自由胜肽KVFGSLAFV(SEQ ID NO:7)、胜肽YLSGADLNL(SEQ ID NO:8)、具有B指示α-胺異丁酸(α-aminoisobutyric acid)的胜肽KLBPVQLWV(SEQ ID NO:6)、胜肽SMPPPGTRV(SEQ ID NO:5)、胜肽IMIGHLVGV(SEQ ID NO:9)、胜肽LLTFWNPPV(SEQ ID NO:4)、胜肽RLLQETELV(SEQ ID NO:2)、具有X及a
分別指示環己基丙胺酸(cyclohexylalanine)及d-丙胺酸的胜肽a
KXVAAWTLKAAa
(SEQ ID NO:1)、胜肽YLQLVFGIEV(SEQ ID NO:3)、胜肽KVAEIVHFL(SEQ ID NO:10)所組成的群組。這些胜肽中的至少兩種可用於本發明,較佳地為至少三種,例如a
KXVAAWTLKAAa
(SEQ ID NO:1)、YLSGADLNL(SEQ ID NO:8)及KVFGSLAFV (SEQ ID NO:7),且更佳為所有上述10種胜肽的組合。在較佳實施例中,胜肽進一步包含一或多種其他胜肽。
在特定實施例中,胜肽可包含選自由FLDEFMEGV(SEQ ID NO:11)、VVMSWAPPV(SEQ ID NO:12)、LLLDDLLVSI(SEQ ID NO:13)、SLADEAEVYL(SEQ ID NO:14)、VLHDDLLEA(SEQ ID NO:15)、GIVEGLITTV(SEQ ID NO:16)、SLFEGIDIYT(SEQ ID NO:17)、FIASNGVKLV(SEQ ID NO:18)、ILNAMIAKI(SEQ ID NO:19)、GLFGDIYLAI(SEQ ID NO:20)、ILDKVLVHL(SEQ ID NO:21)及ACDPHSGHFV(SEQ ID NO:22)所組成之群組的胜肽。
用於描述本說明書的胜肽的命名法依循習知方法,其中胺基呈現於各胺基酸殘基的左邊(胺基(amino-)或N端(N-terminus)且羧基呈現於各胺基酸殘基的右邊(羧基或C端)。雖然沒有具體顯示,但除非另外指出,否則胺基端基團及羧基端基團是假設在生理pH值下呈現的形式。在胺基酸結構式中,各殘基通常由標準三個字母或單一字母符號表是。L型的胺基酸殘基是由大寫單一字母或三個字母符號的大寫第一字母表示,且用於具有D型的胺基酸殘基的D型是由小寫單一字母或小寫三個字母符號表示。例如,符號「a」係指D-丙胺酸。本文所闡述的胜肽的胺基酸序列通常利用標準單一字母符號指示(A,丙胺酸;C,半胱胺酸;D,天門冬胺酸;E,穀胺酸;F,苯丙胺酸;G,甘胺酸;H,組胺酸;I,異白胺酸;K,離胺酸;L,白胺酸;M,甲硫胺酸;N,天門冬醯胺;P,脯胺酸;Q,麩醯胺酸;R,精胺酸;S,絲胺酸;T,羥丁胺酸;V,纈胺酸;W,色胺酸;以及Y,酪胺酸)。除了上述符號之外,本文所使用的單一字母縮寫「B」表示a -胺基丁酸且「X」指示環己基丙胺酸。
懸浮液
本發明使用的胜肽懸浮液可根據包含製備分別含有至少兩種不同胜肽的至少兩種不同溶液的製程來製備。根據本發明的實施例,製備各含有至少一特定胜肽之三種不同溶液A、溶液B及溶液C。具體而言,溶液A為酸性水性介質,溶液B為鹼性水性介質且溶液C為有機介質,特別是DMSO(二甲基亞碸(dimethylsulfoxide))。在較佳實施例中,溶液A、溶液B及溶液C分別至少包含a
KXVAAWTLKAAa
(SEQ ID NO:1)、YLSGADLNL(SEQ ID NO:8)及KVFGSLAFV (SEQ ID NO:7)。
又較佳地,溶液A及/或溶液B進一步包含上述所列胜肽中的至少3種其他胜肽,較佳地,至少5種其他胜肽。更佳地,溶液A及/或溶液B包含所有該7種其他胜肽。個些其他胜肽的每一個將根據其溶解度及與a
KXVAAWTLKAAa
(SEQ ID NO:1)或YLSGADLNL(SEQ ID NO:8)的親和力而包含在溶液A或溶液B中。
因而,在一態樣中,本發明係關於一種用於製造胜肽懸浮液的方法,其包含: a)製備至少三種不同的溶液A、溶液B及溶液C,其中: · 溶液A包含具有X及a
分別指示為環己基丙胺酸及d-丙胺酸的胜肽a
KXVAAWTLKAAa
(SEQ ID NO:1), · 溶液B包含胜肽YLSGADLNL(SEQ ID NO:8), · 溶液C包含胜肽KVFGSLAFV(SEQ ID NO:7),且 · 溶液A及/或溶液B進一步包含選自的具有B指示為α-胺異丁酸的KLBPVQLWV(SEQ ID NO:6)、SMPPPGTRV(SEQ ID NO:5)、IMIGHLVGV(SEQ ID NO:9)、LLTFWNPPV(SEQ ID NO:4)、KVAEIVHFL(SEQ ID NO:10)、RLLQETELV(SEQ ID NO:2)及YLQLVFGIEV (SEQ ID NO:3)中的至少3種其他胜肽; b)混合該溶液,以形成懸浮液;以及 c)將懸浮液的pH調整至約7,且 較佳地,在將任何胜肽加入至溶液B之前,將溶液B的pH調整至12.5及12.9之間。
溶液A較佳地藉由將例如醋酸溶液的酸性水性介質中的胜肽溶液化來製備,較佳為在室溫下。醋酸溶液的濃度可在例如0.1 M至0.3 M的範圍。因而,酸性水性介質具有較佳在2及4之間的pH,更佳地,在2.5及3之間。溶液A的各胜肽可以0.3 mg/ml至4 mg/ml的濃度,較佳地為3~4 mg/ml的濃度存在。較佳地,所有胜肽以相同濃度存在於溶液A中。較佳地,溶液A包含a
KXVAAWTLKAAa
(SEQ ID NO:1)、以及選自由SMPPPGTRV (SEQ ID NO:5)、IMIGHLVGV(SEQ ID NO:9)及KVAEIVHFL(SEQ ID NO:10)所組成的群組中的1個、2個或3個胜肽。在最佳實施例中,溶液A包含a
KXVAAWTLKAAa
(SEQ ID NO:1)、SMPPPGTRV(SEQ ID NO:5)、IMIGHLVGV(SEQ ID NO:9)及KVAEIVHFL(SEQ ID NO:10)。在特定實施例中,溶液A的胜肽由a
KXVAAWTLKAAa
(SEQ ID NO:1)、SMPPPGTRV(SEQ ID NO:5)、IMIGHLVGV(SEQ ID NO:9)及KVAEIVHFL(SEQ ID NO:10)所組成。
此外,溶液B可藉由通常在室溫下將例如氫氧化鈉溶液的鹼性水性介質中的胜肽溶液化來製備。
當放大上述製程時,申請人注意到鹼性溶液中含有的胜肽的其一(即,YLSGADLNL(SEQ ID NO:8))在化學上不夠長期穩定以允許在工業規模上無菌過濾此溶液。
申請人意外地發明,輕微調節應加入YLSGADLNL(SEQ ID NO:8)胜肽的鹼性溶液的pH可避免其降解。因此,本發明的方法適用於製備具有長期穩定性及良好再現性的懸浮液。
確實地,在將任意胜肽加入至其中之前,溶液B的pH調整在12.5及12.9之間,較佳地約12.7。其可藉由使用0.05M的氫氧化鈉溶液來獲得。較佳地,溶液B中的各胜肽總量為0.4至3 mg/ml。更佳地,溶液B中的各胜肽可以2 mg/ml至3 mg/ml的濃度存在。較佳地,所有胜肽以相同濃度存在於溶液B中。較佳地,溶液B包含YLSGADLNL(SEQ ID NO:8)、及選自由KLBPVQLWV(SEQ ID NO:6)、LLTFWNPPV(SEQ ID NO:4)、RLLQETELV(SEQ ID NO:2)及YLQLVFGIEV (SEQ ID NO:3)所組成的群組中的1個、2個、3個或4個胜肽。在最佳實施例中,溶液B包含YLSGADLNL(SEQ ID NO:8)、KLBPVQLWV(SEQ ID NO:6)、LLTFWNPPV(SEQ ID NO:4)、RLLQETELV(SEQ ID NO:2)及YLQLVFGIEV (SEQ ID NO:3)。在特定實施例中,溶液B的胜肽由YLSGADLNL(SEQ ID NO:8)、KLBPVQLWV(SEQ ID NO:6)、LLTFWNPPV(SEQ ID NO:4)、RLLQETELV(SEQ ID NO:2)及YLQLVFGIEV (SEQ ID NO:3)所組成。
最後,溶液C可藉由較佳地在35及40°C之間的溫度下將DMSO中的KVFGSLAFV胜肽(SEQ ID NO:7)溶液化來製備,較佳地在1至11 mg/ml的量,更佳地在10至11 mg/ml的量。較佳地,溶液C中的胜肽可以5 mg/ml至11 mg/ml的濃度存在。在特定實施例中,溶液C中的胜肽由KVFGSLAFV(SEQ ID NO:7)組成。
根據本發明的較佳實施例,溶液A 包含a
KXVAAWTLKAAa
(SEQ ID NO:1)、SMPPPGTRV(SEQ ID NO:5)、IMIGHLVGV(SEQ ID NO:9)及KVAEIVHFL(SEQ ID NO:10),且溶液B包含YLSGADLNL(SEQ ID NO:8)、KLBPVQLWV(SEQ ID NO:6)、LLTFWNPPV(SEQ ID NO:4)、RLLQETELV(SEQ ID NO:2)及YLQLVFGIEV (SEQ ID NO:3)。
除了用作T細胞輔助(T-cell help)的來源的通用pan-DR HTL表位的PADRE之外,所有上述胜肽為自CEA、p53、HER-2/neu及MAGE-2/3所衍生的表位。
然而,溶液A、溶液B或溶液C可進一步包含額外的腫瘤相關抗原胜肽。
如上所述,組合溶液A、溶液B及溶液C,以獲得懸浮液。在較佳實施例中,溶液A、溶液B及溶液C允許在各胜肽的懸浮液中獲得相同濃度的比率組合。較佳地,溶液A、溶液B及溶液C組合,以獲得2~4:3~4:1的A:B:C質量比,更佳為2.9:3.6:1的A:B:C質量比的懸浮液。較佳地,懸浮液中的各胜肽的濃度在0.2及2 mg/ml之間。
根據較佳實施例,在形成懸浮液之前,將溶液冷卻至2至8°C之間的溫度並進行無菌過濾。
較佳地,溶液B在製備後小於8小時,較佳地少於6小時,更佳地不超過4小時與溶液A和溶液C結合。
因此,獲得的懸浮液的pH可調整至生理pH,因而以任何適當地手段調整至約7的pH。胜肽濃度可進一步藉由加入適當地稀釋劑,例如水、生理食鹽水、水性葡萄糖溶液或甘油溶液至懸浮液來調整。
在特定實施例中,在混合溶液A、溶液B及溶液C的步驟之後及/或在調整pH至約7的步驟之前,沒有過濾步驟。
在較佳實施例中,胜肽懸浮液的製造方法的步驟係在飽和的氮氣條件下進行,以避免可能損害懸浮液的胜肽,特別是一或多種可溶性胜肽的任何氧化的風險。
本發明亦關於一種包含由根據本發明的方法製備的懸浮液之無菌容器。較佳地,無菌容器係為玻璃小管。
即用型乳液
(
Ready to Use Emulsion
)
接著,本發明係將胜肽懸浮液與佐劑混合所組成,以獲得油中水乳液,其被認為有助於胜肽向樹突細胞的呈遞。在此類乳液中,含有胜肽的水相以微滴形式裹入在油連續相中,其允許抗原自積存較緩慢地釋出,因此與水中油乳液相比,具有更強的長期免疫性。
「佐劑(adjuvant)」係指本說明書中的可增加因胜肽產生的免疫反應並將此免疫反應導向例如CTL(細胞毒性T淋巴球)反應之化合物或化合物的混合物。佐劑可直接作用於免疫系統或藉由使胜肽適當地遞送至免疫系統而間接地作用。在本發明中,佐劑較佳為包含烴類油(hydrocarbon oil)及油中水乳化劑兩者的油性佐劑。此佐劑藉由所謂「沉積效應(deposition effect)」來作用。烴類油可例如為石蠟油、植物油、鯊烯、鯊烷或礦物油。適當的W/O乳化劑可選自例如甘露醇單油酸酯及山梨糖醇酐單油酸酯。適當的油性佐劑的範例為5-20%甘露醇單油酸酯與80-95%礦物油(購得自SEPPIC的Montanide®
ISA 51)或鯊烯(購得自SEPPIC的Montanide®
ISA 720)的混合物或其類似混合物。在特定實施例中,佐劑為礦物油及甘露醇單油酸酯,特別是Montanide®
ISA 51的混合物。
本發明所使用的佐劑除了上述油性佐劑之外,可替代地為選自微米粒子及奈米粒子,例如PLG、 PLA、PLGA的脂質體及微球體,或其他聚合物,例如明膠、膠原蛋白及聚葡萄胺糖。其他佐劑可包含TLR配位體、類Toll受體配位體(Toll-like receptor ligand)( TLR3及TLR9)、IFN基因(STING)激動劑的刺激劑、如GM-CSF和IL2的細胞介素、碳水化合物、細菌衍生物、礦物鹽類及免疫刺激複合物(ISCOM)。
根據本發明的懸浮液及佐劑係藉由在100至1000rpm轉速下旋轉的混合裝置的方式在低剪切條件下進行混合。例如,轉速可在100至500 rpm,較佳地在150至250 rpm的範圍內,特佳地可為200 rpm。「低剪切(low shear)」係指不以例如(但不限於)由SILVERSON以商品名Silverson®
L4RT或Silverson®
L5M或由IKA WERKE以商品名Ultra-Turrax®
出售的轉子-定子裝置進行混合。接著,乳化步驟係較佳地在2至20分鐘內於低剪切條件,特別是在100至1000 rpm的轉速下進行。在一實施例中,乳化步驟係在2至20分鐘內於100至1000 rpm的轉速的條件下進行。較佳地,本發明的混合步驟或乳化步驟係藉由槳式混合器(paddle-type mixer)或軸流渦輪機的手段進行。例如,混合器可為槳式混合器且具有四節距葉片動葉輪,特別是水平四節距葉片動葉輪。此類的裝置包含其為軸流動葉輪的混合頭,而不是轉子-定子裝置中可見的徑向流動轉子。因此,在一實施例中,混合器可為軸流動葉輪。在其他實施例中,混合器為徑流動葉輪。此外,其不安裝在有孔定子中。
在一較佳實施例中,用於製造即用型胜肽乳液之方法不包含任何具有高剪切的乳化步驟。舉體而言,該方法不包含速度高於7000、6000或5000 rpm的的任何乳化步驟,較佳為不包含速度高於2000 rpm的的任何混合步驟。較佳地,該方法不包含以具有轉子-定子配置的高剪切混合器(Silverson®
Verso)進行任何乳化步驟。
在一較佳實施例中,用於製造即用型胜肽乳液的方法不包含高剪切的任何混合步驟。具體而言,該方法不包含任何速度高於7000、6000或5000 rpm的的任何混合步驟,較佳為不包含速度高於2000 rpm的的任何混合步驟。較佳地,該方法不包含以具有轉子-定子配置的高剪切混合器(Silverson®
Verso)進行任何混合步驟。
較佳地,為了獲得乳液,佐劑在無菌條件下與胜肽懸浮液混合。佐劑:懸浮液重量比可為10:1至1:10的範圍中,較佳為5:1至1:5的範圍且更佳為2:1至1:2的範圍,且又更佳為1:1。
混合步驟或乳化步驟較佳地在10至30°C,較佳為20至25°C的溫度下進行2至30分鐘,例如為5至15分鐘。應理解的是,從所有佐劑加入至混合室時的時刻計算混合的持續時間,其中此添加可以分階段進行。例如,佐劑在30秒至3分鐘內,較佳為1至2分鐘內以100至1000rpm,較佳為100至500rpm,更佳為100至200 rpm範圍的轉速下加入至懸浮液中。接著,該方法可包含在10至30°C下以10至1000 rpm範圍的攪拌速度於30秒至3分鐘的期間將佐劑加入至於混合室的懸浮液中的步驟;在2至20分鐘的期間於10~30℃在100至1000rpm的速度下進行混合的步驟;以及可選地進行回收胜肽乳液的步驟,其中胜肽乳液的體積大於5L。所有或部分的上述混合步驟較佳地在惰性氣氛下,較佳地在氮氣下進行。
因此,可獲得具有體積大於5L,較佳地大於或等於10L的即用型胜肽乳液。其可用於製備用於注射的約8000個小瓶。
根據本發明獲得的胜肽乳液為物理上穩定的。乳液的物理穩定性可藉由在儲存於-20、5及25°C下3個月後測量水滴尺寸來評估,其應與在製造乳液後立即的尺寸實質上沒有不同。微滴尺寸可藉由雷射繞射來測量。根據較佳實施例,乳液的D50為10 ± 2 µm。此外,乳液在相同的儲存條件下不應分開成兩層。
此外,胜肽皆為化學上穩定且亦為生物上穩定。「化學上穩定(chemically stable)」係尤其指胜肽實質上特別是不因氧化及/或脫醯胺作用而降解,且實質上不聚集在一起。胜肽的化學穩定性可在室溫下儲存3個月之後以液相層析法與質譜分析聯用來測定,如下列範例所示。較佳地,乳液中的各胜肽的量在0.1至10 mg/ml,較佳為0.5至1 mg/ml的範圍且與用於製備乳液的量相差不超過10%。該生物穩定性可藉由測量胜肽的免疫原性來評估,例如藉由基因轉殖體內效力測試來評估。
因此,本發明的即用型製劑符合一致製造的工業規定及疫苗產品的品質控制。
乳液可在製造後儲存在2至8°C或甚至冷凍並在使用前達到室溫。此乳液可允許在體積為1至50ml的容器中。
本發明的即用型乳液的優點之一為此乳液可冷凍及解凍,具體而言對乳液的結構沒有任何影響或影響有限。因此本發明關於一種根據本發明的即用型乳液,其可適用於冷凍及解凍,亦即同時保持或保存乳液。
其可作為即用型疫苗進行非經口施予,以誘發對所有對應於使用的胜肽的表位的T淋巴細胞反應。此疫苗可用於治療各種癌症。癌症亦可選自例如NSCLC(非小細胞肺癌(non-small cell lung cancer))及小細胞肺癌的肺癌、黑色素瘤、間皮瘤、乳癌、原發性腦癌(primary brain cancers)、腦轉移癌(brain metastasis cancers)、卵巢瘤、尤其是子宮體(uterine corpus)及/或子宮頸癌的子宮癌、頭頸癌、結腸癌、直腸癌、胃腸癌、腎癌、肉瘤、生殖細胞腫瘤、血癌、淋巴瘤、睾丸癌、胰腺癌及膀胱癌。尤其是,癌症可為結腸癌和非小細胞肺癌(NSCLC),特別是IIIB或IV期及/或表現HLA-A2受體的族群。替代地,癌症亦可選自胰臟癌、膀胱癌或表現由胜肽靶向的腫瘤抗原,特別是CEA、p53、HER-2/neu、MAGE-2及MAGE-3的癌症。對根據本發明製備的乳液進行治療反應的患者病患可藉由例如RT-PCR的不同方法以測量血液樣本中的HLA-2生物標記來識別。
即用型產品可單獨使用於治療癌症或與其他療法組合使用,特別是化療、靶向療法或其他免疫療法,如檢查點抑制劑(checkpoint inhibitors)。
例如,化療可選自順鉑(cisplatin)、卡鉑(carboplatin)、環磷醯胺(cyclophosphamide)、依託泊苷(etoposide)、替尼泊苷(teniposide)、絲裂黴素(mitomycin)、伊立替康(irinotecan)、長春瑞濱(vinorelbine)、依託泊苷(etoposide)、異環磷醯胺(ifosfamide)、替莫唑胺(temozolomide)、氟尿嘧啶(fluorouracil(5FU))、多西他賽(docetaxel)、培美曲塞(pemetrexed)、溫諾平(navelbine)、例如貝伐單抗(bevacizumab)、雷莫蘆單抗(ramucirumab)的靶向腫瘤血管生長的藥物(drugs that target tumor blood vessel growth (VEGF);強的松(prednisone);例如吉非替尼(gefitinib)、埃羅替尼(erlotinib)、阿法替尼(afatinib)的靶向酪氨酸激酶抑制劑(tyrosine kinase inhibitors targeting,EGFR);例如克卓替尼(crizotinib)的ALK抑制劑;色瑞替尼(ceritinib)及其任意組合。
在較佳實施例中,本發明的即用型疫苗用於與檢查點抑制劑組合,特別是CTLA-4抑制劑及/或PD-1或PD-L1抑制劑;IDO抑制劑。以檢查點抑制劑的治療可在以本文所述的即用型疫苗的治療之前、同時或之後進行。
本發明系關於一種套組或產品,其包含:(a)本文所述的治療有效量的即用型疫苗;以及(b)檢查點抑制劑,較佳為CTLA-4抑制劑及/或PD-1或PD-L1抑制劑,以作為用於同時、單獨或依序使用的組合製劑,特別是用於治療癌症。
在較佳實施例中,以檢查點抑制劑的治療是在以本文所述的即用型疫苗的治療之後。
數種PD-1/PD-L1抑制劑已為可用或在臨床開發中。例如,PD-1/PD-L1抑制劑可自包含派立珠單抗(pembrolizumab)(Merk)、尼沃單抗(nivolumab)(Bristol Myers Squibb)、皮立珠單抗(pidilizumab)(Cure Tech)、BMS936559(Bristol Myers Squibb)、MEDI4736(Astra Zeneca)、AMP-224(Astra Zeneca)、AMP-514(Astra Zeneca)、MPDL328OA(Roche)、阿貝單抗(velumab)(亦已知為Merck KgA Serono /Pfizer的MSB0010718C)的非窮舉清單中選擇。例如,PD-1/PD-L1抑制劑可自WO2013/079174中所揭露的內容中選擇,例如,CTLA-4抑制劑可自包含曲美單抗(Tremelimumab)(Pfizer Medimmune)及伊派利單抗(ipilimumab)(BMS)的非窮舉清單中選擇。
即時乳液
(Extemporaneous Emulsion)
本發明亦關於一種用於製備非經口施予的乳液之製程,其包含製備根據本發明的懸浮液,接著將懸浮液與油中水乳化劑混合。
本發明進一步關於一種套組,其包含:含有由根據本發明之方法製備的懸浮液的無菌容器、含有油中水乳化劑的容器,例如小瓶、以及可選的連接器。適當的乳化劑的範例如上所揭露,且較佳地選自甘露醇單油酸酯、山梨糖醇酐單油酸酯及由5-20%的甘露醇單油酸酯或山梨糖醇酐單油酸酯與80-95%礦物油(不完全佛蘭氏佐劑(incomplete Freund's adjuvant)、Montanide®
ISA 51及NH2乳液)或鯊烯(Montanide®
ISA 720)的混合物組成的佐劑。在較佳實施例中,乳化劑包含甘露醇單油酸酯(例如Montanide®
ISA 51)。套組可進一步包含連接器。
接著,如上所獲得的懸浮液可與油中水乳化劑混合,以獲得油中水乳液,其被認為有助於胜肽向樹突細胞的呈遞。在此類型的乳液中,含有胜肽的水相以微滴的形式被包入油連續相中,與水中油乳液相比,其允許從積存更慢地釋放抗原,並因此具有更強的長期免疫性。乳化劑的範例為甘露醇單油酸酯、山梨糖醇酐單油酸酯及由5-20%的甘露醇單油酸酯或山梨糖醇酐單油酸酯與80-95%礦物油 (不完全佛蘭氏佐劑、Montanide®
ISA 51及NH2乳液)或鯊烯(Montanide®
ISA 720)所組成的佐劑。根據本發明的較佳實施例,乳化劑為甘露醇單油酸酯(8-12%)與礦物油 (88-92%)的混合物,其可購得自SEPPIC的商品名Montanide®
ISA 51。據推測,礦物油僅為部分代謝,使其比非礦物油類佐劑更有效誘導免疫反應,特別是在免疫原弱的情況下。通常,為獲得乳液,在無菌條件下,將上述乳化劑的任意的一體積與一體積的胜肽懸浮液混合。
產生的乳液可為「床旁(bedside)」製劑,其可在要治療病患之前即時製備。更具體而言,乳液可利用連接至含有乳液的注射器及含有乳化劑的另一注射器之連接器,根據下列檢查的過程即時地製備:20個慢循環(每循環9s-180s),接著40個快速循環(20s)。乳化劑及懸浮液較佳地儲存在室溫以下的溫度並在混合之前立即地達到室溫。產生的乳液可自製備乳液的8小時內,較佳為4小時內注射給病患。
乳液可為非經口施予並使用作為疫苗,以引發對所有對應於使用的胜肽的表位的T淋巴細胞反應。此疫苗可使用於治療各種癌症,特別是結腸癌和非小細胞肺癌(NSCLC),特別是IIIB或IV期及/或表現HLA-A2受體的族群。癌症亦可選自胰臟癌、膀胱癌或表現由胜肽靶向的腫瘤抗原,特別是CEA、p53、HER-2/neu、MAGE-2及MAGE-3的癌症。即用型產品可單獨使用於治療癌症或與其他療法組合使用,特別是化療、靶向療法或其他免疫療法,如檢查點抑制劑,具體而言如上所揭露。
本發明將根據以下範例而更易理解,該範例係僅用於說明的目,並不意圖限制本發明的範圍,本發明的範圍係由所附發明申請專利範圍所限定。
範例
範例
1
:根據本發明的懸浮液的製備
10個胜肽係由利用標準Boc或Fmoc固相化學的PolyPeptide(San Diego, CA)合成:a
KXVAAWTLKAAa
(SEQ ID NO:1) = MPS-7, SMPPPGTRV (SEQ ID NO:5) = MPS-103, IMIGHLVGV (SEQ ID NO:9) = MPS-214, KVAEIVHFL (SEQ ID NO:10) = MPS-215, YLSGADLNL (SEQ ID NO:8) = MPS-200, KLBPVQLWV (SEQ ID NO:6) = MPS-102, LLTFWNPPV (SEQ ID NO:4) = MPS-213, RLLQETELV (SEQ ID NO:2) = MPS-112, YLQLVFGIEV (SEQ ID NO:3) = MPS-106,以及 KVFGSLAFV (SEQ ID NO:7) = MPS-216。
這些胜肽藉由HPLC進行純化且其身分藉由質譜法驗證。
這些溶液如表1所示進行製備。
溶液1及溶液2在室溫下利用渦流攪拌及/或音波震動幾分鐘來製備,且溶液2加熱在37°C下利用渦流攪拌來製備。接著,這些溶液在2~8°C下儲存長達四個小時,以評估它們在其工業製造過程中潛在保存期間的降解。
降解藉由耦接有UV檢測的液相層析法及質譜法評估。所進行的分析的結果總結在表2中。
因此,上述溶液在2~8°C下儲存小於4小時,接著進行無菌過濾並以2.9:3.6:1的A:B:C質量比混合在一起,以獲得懸浮液,將其pH藉由加入0.2 ml的62.5 mM磷酸鈉溶液及0.5 M NaOH溶液調整至7。
懸浮液於無菌小瓶中儲存在-20°C。
範例
2
:比較實驗
除了將氫氧化鈉的量從0.10M(如WO 2004/094454中所述)改變為0.013M之外,胜肽溶液的製備與範例1中所述的溶液2相同。
評估這些介質在2~8℃儲存2小時後對於溶解胜肽並防止其降解的能力。結果總結在表3中。
自此表中,可推導出處於12.4或低於12.4的pH不能使胜肽適當地增溶,而處於13或13以上的pH導致胜肽的其一的降解。進行質譜分析,以鑑定形成的降解產物。發現Asn或Gln側鏈分別水解成Asp及Glu。此實驗證實溶液2的pH應調整至12.5~12.9。
範例3:懸浮液的穩定性
如下所述設置額外的測試,以評估可能的胜肽聚集。此方法可監測胜肽聚集,且為敏感、特異且準確的。其適用於監測在製造期間或儲存期間可能發生的結構及質量的修飾或變化。進行液相層析法-質譜法(LC-UV/MS),以確認胜肽的身份以及其之間不存在的共價鍵。儘管存在部分胜肽的沉澱,該方法發展用以確認胜肽之間不存在的聚集。其目的是確定在下列不同條件下儲存9個月期間,範例1的懸浮液中所含有的胜肽之間是否可能建立任何共價鍵:-20°C;+5°C及+25°C。
各胜肽藉由UV光譜及質量中的的保留時間來識別。
層析條件
管柱:Advance Bio Peptide Mapping LC管柱,2.1*250 mm,2.7µm,C18,120Å,Agilent reference n°651750-902 檢測: 215 nm及280 nm 流速:0.3 ml/min 注入量:5µl 運行時間:100 min 管柱溫度:35°C ± 2°C 樣品溫度:5°C 針頭清洗:二甲基亞碸(DMSO)中的0.1% 三氟乙酸(Trifluoroacetic acid,TFA) 移動相:溶析液A:5%乙腈(acetonitrile)中0.2% TFA 溶析液B:95% 乙腈中0.2% TFA
樣品溶液的製備
將含有範例1的懸浮液的1個小管(~1ml)的含量轉移至10 ml容積燒瓶並以DMSO中的0.1% TFA完成體積。為了確定確切的樣品重量,在取樣前後稱量小瓶。
範例1的懸浮液藉由液相層析/質譜(LC/MS)方法來分析。
顯示所檢測到的所有胜肽在所有儲存條件下所獲得的結果。不論儲存條件如何,在層析圖之間無顯著差異。相對UV峰面積並無改變。整體MS掃描沒有偵測到對應於共價聚集的高分子量的潛在質量的額外質量。此表示在3個月儲存的期間在胜肽之間沒有建立共價鍵。
此分析的結果為在懸浮液中沒有觀察到胜肽之間的隨後導致化學凝集的共價鍵。
在3個儲存條件(-20°C、 +5°C及+25°C)下3個月之後,觀察到的滯留時間及分子量(MW)完全對應於活性成分胜肽且保持在分批釋出時確定的規格水平內。該結果證實在製造及儲存期間不存在聚集且在懸浮液中沒有發生胜肽之間的共價鍵。
範例
4
:根據本發明的即時
W/O
乳液的製備
為了製備可注射臨床產品,油中水乳液係藉由將範例1的懸浮液與油中水乳化混合物(由SEPPIC供應的Montanide®
ISA 51,在2~8°C的黑暗下儲存於小瓶中)以1:1質量比,其相當於0.9 ml的胜肽懸浮液及1.1 ml的乳化劑混合而形成。具體而言,在混合並分別轉移至注射器之前,將懸浮液及乳化劑立即地回到室溫。藉由連結至注射器的塑膠連接器的方式即時地製備乳液。交替緩慢地推進注射器的柱塞各20次,接著高速推動各40次。1 ml的此乳液可自任何注射器以皮下方式注射給患者。
範例
5
:根據本發明的即用型
W/O
乳液的製備
為了製備可注射臨床產品,油中水乳液係藉由將範例1的懸浮液與油性佐劑(由SEPPIC供應的Montanide®
ISA 51)以1:1質量比混合而形成。為了製備乳液,首先該裝置的混合袋用氮氣充氣,以在操作中提供惰性氣體覆蓋層。過濾5200g的乳化劑,接著在無菌條件下轉移至包含軸流渦輪機的Allegro®
混合器的混合室中。葉輪的轉速設為200 rpm,接著上述的5200g的懸浮液在無菌條件下緩慢地(在1~2分鐘內)加入至混合式。繼續攪拌5分鐘。獲得具有280mPa.s黏度且可容易經由1mL注射器的26 Ga針頭轉移的無可見顆粒的白色乳液。
範例
6
:製備利用不同攪拌時間的乳液
如上表所示,其可推導出無論攪拌時間如何,各種胜肽的濃度保持在0.49~0.59mg/ml範圍內。因此,乳液可以僅使用5分鐘的短攪拌時間來製備。
範例
7
:乳液的化學穩定性
在根據範例5所製備的乳液中所含的胜肽的化學穩定性以下述的方法來評估。
精稱0.9g的範例5的乳液樣品並與DMSO中的0.1%TFA混合,以填充5mL容積燒瓶。接著,將混合物渦流2分鐘並在4000 rpm下離心7分鐘。接著,藉由利用下列層析條件的液相層析法/質譜法(LC/MS)分析下層: 管柱: Advance Bio Peptide Mapping LC column, 2.1 x 250 mm, 2.7µm, C18, 120Å, Agilent®
reference n°651750-902 or equivalent 檢測:215 nm 及280 nm 流速:0.3 ml/min 注入量:5µl 運行時間:100 min 管柱溫度:35°C ± 2°C 樣品溫度:5°C 針頭清洗:二甲基亞碸(DMSO)中的0.1% 三氟乙酸 (TFA) 移動相:溶析液 A: 0.2% TFA in 5% 乙腈 溶析液 B: 0.2% TFA in 95% 乙腈 梯度表:
標準溶液藉由將0.9 mL的範例1所述的分批懸浮液與1.1mL的Montanide ISA 51轉移至10.0mL 容積燒瓶,接著將上述混合物渦流並離心來製備。因此,所獲得的下層以上述相同的條件進行分析。
各胜肽的濃度利用下公式以mg/g表示: A 0.9X 1 濃度(mg/g) = --------- x ----------- x 5 x ---------- S 10 W
其中, A:樣品溶液中的各胜肽的峰面積 S:標準溶液中的各胜肽的峰面積 W:以g表示的樣品重
在不同條件下儲存的範例5的乳液樣品所獲得的結果顯示,在所有儲存條件下,檢測到的所有胜肽在層析圖之間沒有顯著差異,其表示在乳液中觀察到的胜肽之間沒有共價鍵。此外,相對的UV峰面積沒有改變。整體MS掃描沒有偵測到在高分子量包含潛在質量的額外質量。此表示在不同儲存條件下胜肽之間沒有建立共價鍵或聚集。
範例
8
:乳液的物理穩定性
如範例5所示製備的乳液的各種樣品的微滴尺寸由利用粒度計(Malvern mastersizer 3000E光學系統)的雷射繞射來定義。這些樣品自混合器的不同區域收集。結果以微滴的x%的最大尺寸來表示,亦即Dx。結果總結在下表中。
此實驗顯示微滴尺寸在整個混合器中為均質的,D50為約10μm。
範例
9
:免疫原性
部分胜肽識別為部分或全部沉澱在如範例1所述的製備的懸浮液中: MPS-216 KVFGSLAFV (SEQ ID NO:7) (33%溶解度) MPS-215 KVAEIVHFL (56%溶解度) MPS-106 YLQLVFGIEV (0% 溶解度)
即使在難溶或不溶狀態下加入至組合的各胜肽的免疫原性在HLA A2.1/k基因轉殖小鼠體內進行測試。
執行由免疫斑點分析(Elispot assay)的CTL(細胞毒性T淋巴球)及HLT(輔助T淋巴球)誘導,以測量IFNγ生產量,斑點藉由計算機輔助分析進行記數。
淨斑點/ 106
CD8+細胞(CTL)或CD4+細胞(HTL)的計算為(針對相關胜肽的斑點數量)-(無關胜肽的斑點數量) x 2.5。
從6個獨立實驗累積的數據證實該組合為具有誘導CTL反應的免疫原性。
相對於如MPS 214的非常可溶性胜肽,觀察到的範圍是50~200標準單位。
出乎意料地,在3種低可溶性胜肽[具有56%的溶解度的MPS-215(KVAEIVHFL);具有33%的溶解度的MPS-216(KVFGSLAFV(SEQ ID NO:7));具有0%的溶解度的MPS-106(YLQLVFGIEV)]觀察到相同範圍(50~200 SU)的反應。
在新乳液中的可溶、不溶或低可溶的表位可誘導強烈的CTL反應。在最終乳液中的低可溶性胜肽的溶解度狀態不影響HLA A2基因轉殖模式中的體內免疫原性特性。
範例
10
:比較實驗
除了不同之處在於藉由具有轉子-定子配置的高剪切混合器(Silverson®
Verso)的方式進行混合之外,如範例1所述製備的懸浮液以相同比與相同佐劑混合。
分別使用2000和8000rpm的攪拌速率15分鐘及2分鐘:獲得非常黏稠的乳霜而不能使用作為可注射產品。以相同混合器在5000及8000 rpm所獲得的其他批次導致胜肽降解。特別是,在4°C下儲存6週後觀察到8.5%氧化的胜肽SMPPPGTRV(SEQ ID NO: 5),且在-20°C下儲存仍有2%氧化。此外,胜肽IMIGHLVGV(SEQ ID NO:9)在4°C下儲存6週後觀察到16.5%的氧化,且在-20°C下儲存仍有4%氧化。
此實驗證實高剪切混合器不能製備用於穩定遞送胜肽的可注射乳液。
無。
無。
<110> OSE免疫治療公司(OSE IMMUNOTHERAPEUTICS) <120> 用於胜肽遞送的穩定乳液之製造方法 <130> B2418EP <140> 107102651 <141> 2018-01-25 <150> EP 17305079.0 <151> 2017-01-25 <160> 22 <170> PatentIn version 3.5 <210> 1 <211> 13 <212> PRT <213> 人工序列 <220> <223> 胜肽 <220> <221> MISC_FEATURE <222> (1)..(1) <223> Xaa為d-丙胺酸(d-alanine) <220> <221> MISC_FEATURE <222> (3)..(3) <223> Xaa為環己基丙胺酸(cyclohexylalanine) <220> <221> MISC_FEATURE <222> (13)..(13) <223> Xaa為d-丙胺酸 <400> 1 Xaa Lys Xaa Val Ala Ala Trp Thr Leu Lys Ala Ala Xaa 1 5 10 <210> 2 <211> 9 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 2 Arg Leu Leu Gln Glu Thr Glu Leu Val 1 5 <210> 3 <211> 10 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 3 Tyr Leu Gln Leu Val Phe Gly Ile Glu Val 1 5 10 <210> 4 <211> 9 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 4 Leu Leu Thr Phe Trp Asn Pro Pro Val 1 5 <210> 5 <211> 9 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 5 Ser Met Pro Pro Pro Gly Thr Arg Val 1 5 <210> 6 <211> 9 <212> PRT <213> 人工序列 <220> <223> 胜肽 <220> <221> MISC_FEATURE <222> (3)..(3) <223> xaa為α-胺異丁酸(alpha-aminobutyric acid) <400> 6 Lys Leu Xaa Pro Val Gln Leu Trp Val 1 5 <210> 7 <211> 9 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 7 Lys Val Phe Gly Ser Leu Ala Phe Val 1 5 <210> 8 <211> 9 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 8 Tyr Leu Ser Gly Ala Asp Leu Asn Leu 1 5 <210> 9 <211> 9 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 9 Ile Met Ile Gly His Leu Val Gly Val 1 5 <210> 10 <211> 9 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 10 Lys Val Ala Glu Ile Val His Phe Leu 1 5 <210> 11 <211> 9 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 11 Phe Leu Asp Glu Phe Met Glu Gly Val 1 5 <210> 12 <211> 9 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 12 Val Val Met Ser Trp Ala Pro Pro Val 1 5 <210> 13 <211> 10 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 13 Leu Leu Leu Asp Asp Leu Leu Val Ser Ile 1 5 10 <210> 14 <211> 10 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 14 Ser Leu Ala Asp Glu Ala Glu Val Tyr Leu 1 5 10 <210> 15 <211> 9 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 15 Val Leu His Asp Asp Leu Leu Glu Ala 1 5 <210> 16 <211> 10 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 16 Gly Ile Val Glu Gly Leu Ile Thr Thr Val 1 5 10 <210> 17 <211> 10 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 17 Ser Leu Phe Glu Gly Ile Asp Ile Tyr Thr 1 5 10 <210> 18 <211> 10 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 18 Phe Ile Ala Ser Asn Gly Val Lys Leu Val 1 5 10 <210> 19 <211> 9 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 19 Ile Leu Asn Ala Met Ile Ala Lys Ile 1 5 <210> 20 <211> 10 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 20 Gly Leu Phe Gly Asp Ile Tyr Leu Ala Ile 1 5 10 <210> 21 <211> 9 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 21 Ile Leu Asp Lys Val Leu Val His Leu 1 5 <210> 22 <211> 10 <212> PRT <213> 人工序列 <220> <223> 胜肽 <400> 22 Ala Cys Asp Pro His Ser Gly His Phe Val 1 5 10
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Claims (15)
- 一種用於製造工業規模的即用型胜肽乳液之方法,其包含於100至1000rpm之間的轉速,在2~20分鐘期間的低剪切條件下將至少二胜肽的一懸浮液與至少一佐劑進行乳化的步驟,其中該方法不包括任何高速混合步驟,特別是在7000rpm以上的高速混合步驟。
- 如請求項1所述之方法,其中該至少二胜肽包含至少一可溶性胜肽及至少一非可溶性胜肽。
- 如請求項1或2所述之方法,其中該至少二胜肽係選自由胜肽KVFGSLAFV(SEQ ID NO:7)、胜肽YLSGADLNL(SEQ ID NO:8)、具有B指示為α-胺異丁酸的胜肽KLBPVQLWV(SEQ ID NO:6)、胜肽SMPPPGTRV(SEQ ID NO:5)、胜肽IMIGHLVGV(SEQ ID NO:9)、胜肽LLTFWNPPV(SEQ ID NO:4)、胜肽RLLQETELV(SEQ ID NO:2)、具有X及a分別指示為環己基丙胺酸及d-丙胺酸的胜肽aKXVAAWTLKAAa(SEQ ID NO:1)、胜肽YLQLVFGIEV(SEQ ID NO:3)及胜肽KVAEIVHFL(SEQ ID NO:10)所組成的群組。
- 如請求項3所述之方法,其中該懸浮液包含胜肽KVFGSLAFV(SEQ ID NO:7)、胜肽YLSGADLNL(SEQ ID NO:8)、胜肽KLBPVQLWV(SEQ ID NO:6)、胜肽SMPPPGTRV(SEQ ID NO:5)、胜肽IMIGHLVGV(SEQ ID NO:9)、胜肽LLTFWNPPV(SEQ ID NO:4)、胜肽RLLQETELV(SEQ ID NO:2)、具有X及a分別指示為環己基丙胺酸及d-丙胺酸的胜肽aKXVAAWTLKAAa(SEQ ID NO:1)、胜肽YLQLVFGIEV(SEQ ID NO:3)及胜肽 KVAEIVHFL(SEQ ID NO:10)的組合。
- 如請求項1所述之方法,其中該至少一佐劑係由一烴類油與一油中水乳化劑所組成。
- 如請求項5所述之方法,其中該烴類油係選自石蠟油、植物油、鯊烯、鯊烷或礦物油,且該油中水乳化劑係選自甘露醇單油酸及山梨糖醇酐單油酸酯。
- 如請求項5所述之方法,其中該至少一佐劑與該至少二胜肽的該懸浮液的重量比係自10:1至1:10的範圍。
- 如請求項1所述之方法,其中所有或部分的混合步驟係在惰性氣氛下。
- 如請求項1所述之方法,其中該乳液的體積係大於5L。
- 如請求項3所述之方法,其中該至少二胜肽的該懸浮液係由一方法所製備,該方法包含:a)製備不同的至少三個溶液A、溶液B及溶液C,其中:●溶液A為酸性水性介質且包含具有X及a分別指示為環己基丙胺酸及d-丙胺酸的胜肽aKXVAAWTLKAAa(SEQ ID NO:1),●溶液B為在加入任何胜肽之前的pH為12.5與12.9之間的鹼性水性介質,且該溶液B包含胜肽YLSGADLNL(SEQ ID NO:8),●溶液C為DMSO且包含胜肽KVFGSLAFV(SEQ ID NO:7),及●該溶液A及/或溶液B進一步包含選自具有B指示為α-胺異丁酸的胜肽KLBPVQLWV(SEQ ID NO:6)、SMPPPGTRV(SEQ ID NO:5)、IMIGHLVGV(SEQ ID NO:9)、LLTFWNPPV(SEQ ID NO:4)、KVAEIVHFL(SEQ ID NO:10)、RLLQETELV(SEQ ID NO:2)及YLQLVFGIEV(SEQ ID NO:3)的額外的至少三胜肽; b)將該至少三個溶液A、溶液B及溶液C混合,以形成該懸浮液;以及c)將該懸浮液的pH調整至約7。
- 如請求項10所述之方法,其中該溶液A包含aKXVAAWTLKAAa(SEQ ID NO:1)、SMPPPGTRV(SEQ ID NO:5)、IMIGHLVGV(SEQ ID NO:9)及KVAEIVHFL(SEQ ID NO:10),且該溶液B包含YLSGADLNL(SEQ ID NO:8)、KLBPVQLWV(SEQ ID NO:6)、LLTFWNPPV(SEQ ID NO:4)、RLLQETELV(SEQ ID NO:2)及YLQLVFGIEV(SEQ ID NO:3)。
- 一種根據如請求項1至11中任一項所述之方法可獲得的即用型乳液。
- 如請求項12所述之即用型乳液,其中在該即用型乳液中的各胜肽的量為0.1至10mg/ml,且與用於製備該即用型乳液的量相差不超過10%。
- 如請求項12或13所述之即用型乳液,其中該即用型乳液的D50為10±2μm。
- 如請求項12或13所述之即用型乳液,其用於在表現HLA-A2受體的患者中以單獨或與化療、靶向療法組合的方式治療癌症。
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WO2020127367A1 (en) | 2018-12-21 | 2020-06-25 | Ose Immunotherapeutics | Humanized anti-human-pd-1 antibody |
BR112021012040A2 (pt) | 2018-12-21 | 2021-11-03 | Ose Immunotherapeutics | Molécula anti-pd-1/sirpa bifuncional |
US20230071889A1 (en) | 2018-12-21 | 2023-03-09 | Ose Immunotherapeutics | Bifunctional anti-pd-1/il-7 molecule |
AU2019406453A1 (en) | 2018-12-21 | 2021-07-22 | Ose Immunotherapeutics | Bifunctional molecule directed against human PD-1 |
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Patent Citations (2)
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WO2004094454A2 (en) * | 2003-04-18 | 2004-11-04 | Idm Pharma, Inc. | Hla-a2 tumor associated antigen peptides and compositions |
WO2016070928A1 (en) * | 2014-11-06 | 2016-05-12 | Orphan Synergy Europe - Pharma | Therapeutic multi-peptides t specific immune therapy for treatment of brain metastasis |
Non-Patent Citations (1)
Title |
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期刊 Jerome Aucouturier Montanide ISA 720 and 51: a new generation of water in oil emulsions as adjuvants for human vaccines Expert Review of Vaccines 1(1) 2002 111-118 * |
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